Pharmacokinetics Lecture Notes PDF

SM CPT PHARMACOKINETICS MB ChB Year 1 – Clinical Pharmacology & Therapeutics Professor Simon Maxwell Clinical Pharmacology Unit, University of Edinburgh...

SM CPT PHARMACOKINETICS MB ChB Year 1 – Clinical Pharmacology & Therapeutics Professor Simon Maxwell Clinical Pharmacology Unit, University of Edinburgh [email protected] SM CPT LEARNING OUTCOMES At the end of the lecture you should be able to explain: What is pharmacokinetics? How are drugs absorbed into the body? How are drugs distributed in the body? How are drugs metabolised in the body? How are drugs excreted from the body? What is the relationship between drug concentration and time (single dose)? What is the relationship between drug concentration and time (repeated doses)? SM CPT What is pharmacokinetics?  Pharmacokinetics is often summarised as the study of ‘what the body does to SM CPT a drug’ to distinguish it from pharmacodynamics (the study of ‘what a drug does to the body’). Both of these major components of clinical pharmacology are important for clinicians because they describe how the dosage regimen that they prescribe will ultimately be related to the pharmacological effects that they might see in their patients. It is the science of pharmacokinetics that explains how the drug concentration will vary over time after a dose has been administered while pharmacodynamics explains how that concentration is translated into a pharmacological response. Pharmacokinetics can be defined more specifically as the study of: SM CPT Definition of pharmacokinetics Pharmacokinetics can be defined as the study of the rate and extent to which drugs are absorbed into the body and the rate and extent to which drugs are absorbed into the body distributed to the body tissues and distributed to the body tissues the rate and pathways by which drugs are eliminated from the the rate and pathways by which drugs are eliminated from the body by body by metabolism and excretion the relationship between time and plasma drug concentration metabolism and excretion Pharmacokinetics - 'what the body does to a drug’ the relationship between time and plasma drug concentration Pharmacodynamics - 'what a drug does to the body' Pharmacokinetics (is sometimes abbreviated to PK) and embraces the study of SM CPT four phases of drug handling: how drugs are absorbed into the body; how absorbed drugs are distributed around the tissues; how drugs are metabolised (notably in the liver), and how drugs or their metabolites are excreted (notably from the kidney). Together these four stages are sometimes abbreviated to A–D–M–E.  All prescribers need a basic understanding of the principles of SM CPT Why is pharmacokinetics relevant for prescribers? Drug dosage regimen pharmacokinetics because they influence the best choice of route of Pharmacokinetics administration and the selection of drug doses. Differences in pharmacokinetic ‘What the body does to the drug’ Drug concentration in plasma handling (rather than pharmacodynamics) explain most of the variation in the Drug concentration around site of action Physiological factors age, sex, body weight, organ function effect of the same drug, given in the same dosage to different patients. Therefore, it follows that they also explain many adverse drug reactions and External factors food, other drugs Pharmacodynamics ‘What the drug does to the body’ episodes of failed therapy. For instance, an excessive response can result from Drug effect Clinical response inhibited liver metabolism or delayed excretion owing to impaired renal function, whereas a suboptimal response can result from incomplete absorption or enhanced first-pass metabolism. Pharmacokinetic handling of a drug will also be influenced by physiological factors (e.g. age, sex, body weight, organ function) and external factors (e.g. food, other drugs). Many of these unwanted adverse effects can be avoided if prescribers make judicious dose selections in advance, by anticipating likely pharmacokinetic variations. Examples might include: prescribing higher doses for patients of increased body mass or vice versa prescribing reduced doses of drugs that are excreted by the kidney for elderly patients prescribing reduced doses of drugs that depend on hepatic metabolism for patients with liver disease (or avoiding such drugs altogether). SM CPT How are drugs absorbed into the body? Drugs can be absorbed into the body by various different routes. Most drugs SM CPT are administered orally (PO). If they are successfully swallowed, they pass down the oesophagus and enter the stomach before being transmitted to the small bowel. There, they can be absorbed across the large surface area of the jejunal mucosa before entering the portal circulation and travelling to the liver. From the liver, they travel to the heart and systemic circulation via the hepatic vein. The involvement of the small bowel mucosa means that this is often referred to more specifically as the ‘enteral’ route. However, not all drugs passing the lips are absorbed in this way. Buccal tablets, placed between the lip and gum, and sublingual tablets or sprays placed beneath the tongue lead to drug absorption directly into the systemic circulation across the oral mucosa, avoiding the portal venous system and liver. Exposure to the portal system and liver can also be avoided by rectal (PR) administration. Drugs can be given by ‘parenteral’ routes that do not involve absorption across the gastrointestinal mucosa. Intravenous (IV) injection of a drug directly into a vein bypasses the gastroenterological absorption process. It ensures that all of the dose is immediately available for distribution to the tissues and leads to a rapid onset of drug action. Intramuscular (IM) injection into muscle tissue usually leads to a rapid effect but, the rate of absorption into the systemic circulation is highly dependent on muscle blood flow. Subcutaneous (SC) injection underneath the skin usually allows for rapid absorption of lipid- soluble drugs from subcutaneous fat. Some drugs can be administered by inhalation (INH). This may include volatile compounds such as anaesthetic gases, drugs dissolved in solutions that are administered to the airways mucosa as an aerosol or drugs that are formulated as dry powders that are also inhaled onto the bronchial mucosal surface. The skin can be an effective route of absorption for some drugs. Transdermal administration allows drugs intended for systemic distribution to be continuously absorbed across the epidermis from adhesive skin patches over many hours. Topical administration is preferred for drugs that are intended to have a local site of action. The commonest examples are lotions, creams, ointments or pastes that are applied to the skin or mucous membranes. The advantage of topical application is that the exposure of other parts of the body to the drug is minimised. The route of administration is an important influence on the rate of absorption: in general this ranges from instantaneous after intravenous administration, rapid after inhalation, fast after intramuscular injection, slow after oral administration and prolonged after application of a drug to the skin.  Only a proportion of a drug dose that is administered by the oral route SM CPT eventually becomes bioavailable for distribution to the body tissues. That is because, even if the whole dose is swallowed, some of the molecules may be lost because of destruction by gastric acid, binding to food or physicochemical characteristics that limit their absorption across the mucosa. However, the most important limitation upon absorption is so-called ‘first-pass’ metabolism by enzymes in the intestinal wall and the liver. The cells of the intestinal wall contain a large number of enzymes capable of metabolising drug molecules passing through them. Examples include monoamine oxidase (metabolising sympathomimetic amines such as tyramine), L-aromatic amino acid decarboxylase (metabolising the anti- Parkinsonian drug levodopa), and the cytochrome P450 isoform 3A4 (metabolising the anti-epileptic carbamazepine), as well as enzymes responsible for Phase II conjugation reactions. They also contain membrane transporters, such as P-glycoprotein, which can return drug molecules to the intestinal lumen. The effect of these processes can be so extensive that no active drug reaches the systemic circulation after oral administration. However, it is passage of the portal blood flow through the liver that accounts for most first-pass metabolism of drugs given orally, because of the liver’s greater enzyme content, notably the Phase I metabolising enzymes of the cytochrome P450 system. Examples of drugs that have a high hepatic extraction include tricyclic antidepressants (e.g. amitriptyline, imipramine), calcium-channel blockers (e.g. nifedipine, diltiazem), lipid-soluble beta- blockers (e.g. labetalol, propranolol) and opioid analgesics (e.g. morphine, pethidine). While some of these drugs have active metabolites that contribute to their pharmacological effects, the pharmacologically equivalent oral dose of most is substantially greater than the intravenous dose to allow for hepatic  first-pass extraction. Some drugs (e.g. isoprenaline) are so extensively metabolised that they are inactive when given by the oral route, however large the dose. In summary, to be successful after oral administration a drug must be swallowed, survive gastric acid, avoid unacceptable food binding, be absorbed across the small bowel mucosa and survive intestinal and hepatic first-pass metabolism. The extent to which a drug dose survives to enter the circulation The impact of first-pass metabolism in the intestine and liver on drug SM CPT absorption can be avoided by administering drugs to other absorptive surfaces in the gastrointestinal tract that do not involve drainage into the portal circulation. These include the buccal and sublingual mucosa and he rectal mucosa. Buccal administration involves the tablet being placed between the upper lip and gum and held there until it dissolves. Examples include glyceryl trinitrate (for acute angina), prochlorperazine (an anti-emetic), and fentanyl (an opioid analgesic). Sublingual administration involves placing a tablet beneath the tongue and holding it there until it dissolves. Examples include glyceryl trinitrate and buprenorphine (another opioid analgesic). Some patients using glyceryl trinitrate find taking tablets by this route difficult and prefer to use an aerosol spray formulation directed into the mouth, which achieves an equivalent effect. Both the buccal and sublingual routes involve drug molecules being absorbed into the capillaries of the oral circulation from where they drain onto the superior vena cava before returning to the heart and entering the systemic circulation.  Rectal administration is commonly used for non-absorbed drugs intended to act locally to soften the faeces in patients who are constipated, but it is also a potential route of systemic drug absorption. Rectal drug administration is particularly useful for patients who cannot swallow or who are vomiting, where there is no suitable injectable formulation (e.g. paracetamol), or where a rapid effect is necessary in an unconscious patient, in whom intravenous access is uncertain (e.g. diazepam for epileptic seizures). The lower two-thirds of the rectum is drained by the inferior and middle haemorrhoidal veins, which are tributaries of the inferior vena cava. Therefore, drugs administered by this route return to the heart and enter the systemic circulation directly, avoiding first-pass metabolism in the jejunal wall and liver. Intravenous administration is the most direct route of entry for drug SM CPT molecules in to the systemic circulation. The needle obviates the need for the drug to cross a membrane or be exposed to first-pass metabolism before entering the systemic circulation, so there are no concerns about pre-systemic loss. The entire dose is bioavailable and a high drug concentration is rapidly achieved. This intravenous route is therefore ideal for very ill patients where a rapid,  most commonly administered orally but many are also available for reconstitution into solutions that a suitable for injection (e.g. penicillins, cephalosporins, metronidazole). The latter formulations are to be preferred in more severe infections when prescribers need to be assured that antimicrobial drug concentrations will be achieved without delay or when there are concerns about absorption because of vomiting or gastric stasis. Other examples of drugs where the intravenous route is preferred include urgent administration of powerful opioid analgesics, anti-arrhythmic drugs, and diuretics. However, where a drug has a low therapeutic index (i.e. a narrow range between the lowest effective dose and the highest safe dose), a high drug concentration in plasma may not be desirable. In this case, an intravenous infusion may be preferred so that the dose can be administered over a longer period, thereby reducing the peak concentration achieved. This figure illustrates the difference in the plasma drug concentration-time SM CPT curves after a single dose of the same drug administered either orally or intravenously. The area under the curve (AUC) for the oral administration is significantly smaller than for the intravenous curve indicating reduced 40 mg.h/L bioavailability. This can be expressed as a percentage (in this example the oral bioavailability of this drug is 12/40 = 30%). It is also notable that the peak 12 mg.h/L concentration is lower and delayed after oral administration. Intravenous administration is therefore preferred in very ill patients for whom the pharmacological effects of drugs are required more urgently. SM CPT How are drugs distributed in the body? For a drug to exert its desired pharmacodynamic effects it must not only be SM CPT absorbed into the body but must also reach its site of action in sufficient concentration. This will depend on the rate and extent of the distribution of drug molecules around the various fluid compartments of the body and into the tissues. An understanding of drug distribution is critical to the drug development process but it is also of importance to prescribers. Many of the adverse effects of drugs occur because of unwanted distribution of drugs to tissues other than the intended site of action. Some important drug interactions occur because drugs affect each other’s distribution, notably by competing with and displacing each other from protein binding. Finally, changes in body composition for physiological reasons (e.g. age, sex), or because of illness, may alter drug distribution and require variation in the dose that is prescribed and administered.  When considering how drug molecules are distributed, the body can be SM CPT thought of as a series of compartments into and out of which drugs can move. The major body compartments are the plasma, the interstitial fluid (extracellular) and the intracellular fluid. Many cells, notably adipocytes, contain large stores of fat, which can be considered as a further separate compartment, the importance of which is related to the lipid-solubility of the drug. Drugs are able to transfer between these compartments by crossing cell membranes, usually by passive diffusion down a concentration gradient, but sometimes by active transport against a gradient. Shortly after absorption of a single dose, drug molecules will move predominantly from plasma to the interstitial and then intracellular fluid. Eventually an equilibrium will be reached when the concentrations in each compartment mean that the rate of entry and exit from each is equal. Without further drug administration this equilibrium will not last because the elimination of the drug from the plasma (by metabolism or excretion) will create a gradient favouring movement of the drug out of the tissues. This distribution of drug molecules between compartments is dependent on their molecular size, lipid solubility, ionisation, binding to plasma proteins, rate of blood flow and special barriers (e.g. the blood-brain barrier). In addition, some drugs have particular affinity for specific tissues. For example, calcium is retained in bones, iodide and the iodine containing anti-arrhythmic drug amiodarone in the thyroid gland and the antibiotic tetracycline in bones and teeth.  The vast majority of drugs cross membranes by simple diffusion. This process SM CPT does not require energy or any specialised transport molecules. The drug molecules simply diffuse through the membrane from an area of high concentration to an area of lower concentration (i.e. down the concentration gradient). They may also diffuse back if a sufficient concentration builds up but this is unlikely because the molecules are either bound at their pharmacological site of action, diffuse across further membranes or are destroyed. To gain access to the membrane the drug must be dissolved in the aqueous solution around it and not be bound to larger molecules such as proteins. The large membrane surface area means that the process of simple diffusion is not saturable (i.e. the rate of transfer will continue to rise with increasing drug concentration). Furthermore, the non-specific nature of the process means that it is not inhibited by other drugs or molecules. The rate of transfer of drug molecules by diffusion will depend on: the concentration gradient the molecule (lipid solubility, degree of ionisation, size) the membrane (thickness, chemical composition) Simple diffusion may also occur in aqueous solution rather than require dissolution into the lipid-soluble membrane. This is possible because many membranes have aqueous pores to facilitate the transport of small molecules and these can also be used by drugs. Pinocytosis (a form of endocytosis) involves invagination of part of the cell membrane and the trapping of a small vesicle containing extracellular constituents within the cell. The vesicle contents can then be released within the cell, or extruded from its other side by fusion with another membrane  (complexed with intrinsic factor) in the terminal ileum. Pinocytosis is also important for the transport of some macromolecules, such as insulin, which crosses the blood–brain barrier by this process. Many drugs are bound to proteins in plasma. Weak acids bind to albumin and SM CPT weak bases to alpha1-acid glycoprotein, whereas steroids bind to globulins. For drugs that display this property, association and dissociation with the protein are rapid and reversible. Binding takes place as soon as drug molecules enter the plasma. Throughout the drug’s residence in the body, until the last molecule has been eliminated (and the plasma contains no drug), the fraction bound will remain unchanged, unless displacement occurs as a result of competition for binding from other drugs or endogenous molecules (e.g. free fatty acids). As the total plasma drug concentration rises, more and more molecules become bound (maintaining a constant fraction). This creates a protected depot of drug in the blood – bound drug molecules cannot leave the plasma because the molecules carrying them are too large to cross the capillary walls, nor can they be metabolised or excreted. As the concentration of unbound drug falls as a result of metabolism or excretion, bound drug dissociates to maintain a constant fraction, releasing more drug molecules for elimination. Drugs that are more than 90% bound to plasma proteins include the  antiplatelet drug aspirin, the anxiolytic diazepam, the anticonvulsant phenytoin and the anticoagulant warfarin. Drugs that are highly bound to plasma proteins persist in the body for longer than those less heavily bound, have less efficient distribution and lower therapeutic activity, and are less available for dialysis after toxic doses. They may also displace each other when competing for binding sites. The table gives some examples of drugs that are highly bound to plasma proteins. The concepts of drug diffusion and protein binding can be further illustrated SM CPT by considering the volume of distribution (Vd) of three different drugs following a 500 mg intravenous injection. For Drug A, after a short period of time to allow for distribution, the plasma concentration of the drug is found to be 100 mg/L. Using the previous equation, the volume of distribution is calculated as 5 L. This implies that most of the drug must still be in the plasma compartment, probably because it is highly bound to circulating plasma proteins, which are unable to cross the endothelium into the interstitial space. For Drug B, the plasma concentration was found to be 31 mg/L giving a volume of distribution of around 16 L. This implies that the drug has been able to distribute throughout the extracellular fluids but not enter cells. For Drug C, the plasma concentration was found to be 5 mg/L giving a volume of distribution of around 100 L. This implies that the drug has been able to distribute throughout the extracellular and intracellular fluids. Indeed, the fact that the overall volume is greater than that of the body suggests that a lot of the drug has been highly bound within the intracellular space.  The table shows the volumes of distribution of some drugs in common use. The volume of distribution (Vd) is expressed either as an absolute volume in a 70 kg adult or as the volume per kilogram. In a 70 kg adult the approximate volume of total body water is 42 litres i.e. 0.6 L/kg. SM CPT How are drugs metabolised in the body? The principal organ of drug metabolism is the liver, which is well-perfused SM CPT and contains a high concentration of metabolising enzymes in the smooth endoplasmic reticulum. Collectively, these are often referred to as the cytochrome P450 system, a superfamily of enzymes containing haem as a cofactor. The liver has a special anatomical relationship with the gastrointestinal tract. The liver not only receives arterial perfusion from the systemic circulation but  returning from the stomach, small bowel and large bowel. The portal blood passes through the sinusoids of the liver lobules before entering the central vein and draining into the hepatic vein. This means that any absorbed chemicals must survive potential metabolism in the liver before being able to reach the systemic circulation for wider distribution around the body. Even before a drug can enter the portal circulation it has to pass across the small bowel mucosa, which is also a site of significant exposure to drug metabolising enzymes. The combination of the metabolism of drugs in the small bowel mucosa and liver is often referred to as first-pass metabolism and may result in the loss of a significant proportion of drug doses that are administered by the oral route. Drugs such as the calcium channel blocker verapamil and glyceryl trinitrate are subject to extensive first-pass metabolism and so have low oral bioavailability. In other words, only a small fraction of an orally administered dose enters the systemic circulation as the pharmacologically active parent drug molecule. Other sites of drug metabolism include the lungs, kidneys, and the skin. Metabolism (sometimes referred to as biotransformation) is the conversion of SM CPT a substance from one form to another by the actions of enzymes or organisms. Its dual purpose is to transform the drug molecule into an inactive metabolite that poses no threat to cellular function and convert that metabolite into a chemical form that can be excreted from the body. Most drugs have to be lipid-soluble in order to be absorbed, cross membranes, move around the body and reach their site of action. However, they cannot  urinary tract or gut and would remain in the body indefinitely. Metabolism reduces lipid solubility and prepares drug molecules for excretion. Metabolism occurs predominantly in the liver and is normally divided into two distinct phases: Phase I (non-synthetic) reactions involve oxidation, reduction or hydrolysis that alters the structure in a way that often prevents or reduces the pharmacological activity of the molecule. Phase II (synthetic) reactions involve conjugation with a natural endogenous constituent, such as glucuronic acid, glutathione, sulphate, acetic acid, glycine or a methyl group, resulting in a product that is more soluble and easy to excrete. The membranes of the smooth endoplasmic reticulum of hepatocytes are the SM CPT CP principal site of metabolism in the liver. When the endoplasmic reticulum is isolated by ultracentrifugation, these membranes break up into smaller vesicles known as microsomes. The largest family of membrane-bound, mixed- function enzymes is called the cytochrome P450 system. The system is so named because of its location (cyto = cell) and the fact that the haem moiety absorbs coloured (chrome) light at a wavelength of 450 nm when it is in the reduced state. Each cytochrome enzyme contains a haem-bound iron at the active site, responsible for binding with oxygen and the drug substrate,  enabling the transfer of one atom of oxygen to the substrate (a mono- oxygenase reaction) in the presence of NADPH, which provides the reducing equivalents to facilitate the reaction. RH + O2 + NADPH + H+ ➔ ROH + H2O + NADP+ The haem group is attached to a protein chain embedded into the membrane. The superfamily of CYP enzymes is divided into four families (CYP1, CYP2, SM CPT CP CYP3 and CYP4), each of which is further divided into five subfamilies (A to E). The most important subfamilies are CYP1A, CYP2B, CYP2C, CYP2D, CYP2E and CYP3A. Of these, CYP3A is the most abundant hepatic subfamily, responsible for the metabolism of more drugs than any other. Individual enzymes (isoforms) within each subfamily are also numbered. The figure shows an approximate proportion of drugs metabolised by the most important isoforms. Individual drugs may be metabolised by more than one isoform, although most are better substrates for one isoform than another. This table provides just a few common examples of drugs that undergo phase I SM CPT CP Phase I drug metabolism metabolism catalysed by the most important cytochrome P450 isoforms. The most important isoenzymes include: CYTOCHROME P450 SYSTEM CYP1A2 caffeine, theophylline, clozapine, olanzapine NSAIDs (e.g. ibuprofen), sulfonylureas (e.g. glipizide), fluoxetine, CYP2C9 amitriptyline, ARAs (e.g. losartan), S-warfarin diazepam, proton pump inhibitors (e.g. omeprazole), clopidogrel, CYP3A4. Substrates include amiodarone, carbamazepine, ciclosporin, CYP2C19 anti-epileptics (e.g. phenytoin), SSRIs (e.g. citalopram) opioids (e.g. codeine), antipsychotics (e.g. haloperidol), Some drugs are metabolised CYP2D6 omeprazole, opioid analgesics, prednisolone, statins, tamoxifen and R- beta-blockers (e.g. propranolol), SSRIs (e.g. fluoxetine) by multiple isoforms CYP2E1 paracetamol, ethanol, general anaesthetics (e.g. halothane) Most drugs are inactivated by cytochrome P450 metabolism but some depend on it for CYP3A4 amiodarone, benzodiazepines (e.g.midazolam), calcium channel blockers (e.g. amlodipine), carbamazepine, chemotherapy (e.g. tamoxifen), immunosuppressants (e.g. ciclosporin), opioid warfarin. activation (e.g. clopidogrel) analgesics, glucocorticoids (e.g. prednisolone), sex hormones (e.g. CYP2D6. Substrates include codeine, morphine, omeprazole tamoxifen and oestradiol), statins (e.g. simvastatin), R-warfarin and many others trazodone.  CYP2C9. Substrates include diclofenac, fluoxetine, nifedipine, tricyclic antidepressants, valproate and S-warfarin. CYP2C19. Substrates include diazepam, omeprazole, propranolol and R- warfarin. CYP2E1. Substrates include paracetamol and alcohol. Phase II reactions involve conjugation of the metabolite formed in a phase I SM CPT Phase II drug metabolism reaction with natural endogenous constituents to form glucuronide, sulfate, acetyl and methyl conjugates. These products are water-soluble and therefore suitable for excretion either in urine or bile. It should be noted that there are some drugs, and their phase I metabolites, that are sufficiently water-soluble to be excreted without the need for Phase II conjugation reactions. Although phase II reactions normally involve conjugation of phase I metabolites there are exceptions, where it is the parent drug which is subject to a phase II conjugation reaction. An important example in clinical practice is the opioid analgesic morphine, which is conjugated to form morphine-6- glucuronide, a phase II metabolite that unusually retains its pharmacological activity at opioid receptors. The antituberculous drug isoniazid is initially acetylated in a Phase II reaction before then being metabolised in a Phase I hydrolysis reaction. The enzymes that conjugate drugs with glucuronide are found in the endoplasmic reticulum close to the cytochrome P450 system enzymes, whereas those conjugating with sulfate are found in the cytosol. Although  phase II conjugation reactions mainly take place in the liver, there are also similar reactions occurring in the small bowel mucosa. The duration and intensity of pharmacological action of most lipophilic drugs SM CPT CP are determined by the rate at which they are metabolised to inactive products, most commonly by the cytochrome P450 system. In general, anything that increases the rate of metabolism (e.g. enzyme induction) of a pharmacologically active metabolite will decrease the duration and intensity of the drug action. The opposite is also true (e.g. enzyme inhibition). Conversely, in cases where metabolism converts an inactive pro-drug into an active metabolite (e.g. clopidogrel) drug, faster metabolism results in increased drug concentration and pharmacological effect. In cases where a drug is metabolised into a toxic metabolite (e.g. paracetamol), faster metabolism is associated with an increased risk of toxicity. Several important factors may influence the variation in the rate of drug metabolism between individuals: Genetic variations in cytochrome P450 genes (often caused by single nucleotide polymorphisms at individual alleles) can affect the function of specific enzyme isoforms. Common examples of drugs where a polymorphism causes a significant phenotypic variation in Phase I  conversion of codeine to morphine (at CYP2D6) and the inactivation of warfarin (at CYP2C9). One of the first phenotypic variations in metabolism to be described affected the Phase II acetylation of the antituberculous drug, isoniazid. The population is divided into those who make an efficient or inefficient form of the enzyme responsible for acetylation (N- acetyltransferase). Slow acetylators are more susceptible to isoniazid- induced peripheral neuritis while fast acetylators are more susceptible to hepatic toxicity. Age is another factor that affects drug metabolism. Older patients have a reduced metabolising capacity because hepatic volume and blood flow are decreased. Metabolism is also reduced in neonates because the hepatic microsomal enzyme system is immature, although beyond infancy, some drugs are metabolised faster in children than in adults. There are some important sex differences in drug metabolism because androgens, oestrogens and glucocorticoids affect the expression of CYP enzymes. The metabolism of diazepam, caffeine and paracetamol is faster in women while propranolol and lidocaine metabolism is faster in men. Nutritional status is sometime relevant. Conjugating agents are sensitive to body nutrient level. For example, a low protein diet can decrease the availability of the amino acid glycine. Some disease states, most notably those affecting the liver, are potential causes of altered metabolism. Metabolising capacity is reduced in patients who have established liver disease (e.g. cirrhosis, hepatitis) although the extent or any change is difficult to predict from standard markers of liver disease such as blood tests or imaging. Hepatic metabolism may also be reduced by conditions that affect hepatic blood flow (e.g. shock, heart failure).  other drugs through the cytochrome P450 enzymes. Some interacting drugs induce the production of more cytochrome isoforms by hepatocytes, which has the effect of increasing the rate of Phase I metabolism of other drugs that are metabolised by the same pathway. Conversely, some interacting drugs compete for metabolism through the the same cytochrome isoform, inhibiting the metabolism of competitor drugs. It is important to recognise that there may also be interactions with environmental factors, such as alcohol and tobacco, which induce the metabolism of some isoforms and food components such as grapefruit juice which inhibits the CYP3A4 metabolism of many drugs. The dose of a drug may influence the rate of metabolism through alternative pathways if it is high enough to saturate the metabolising capacity of the primary pathway. The most relevant example in clinical practice is the change in metabolism of paracetamol when taken in overdose. In these circumstances, the normally dominant phase II conjugation pathway is saturated, leading to a greatly increased production of a toxic metabolite via Phase I metabolism. If this rate exceeds the capacity of the liver to detoxify this metabolite severe life-threatening hepatotoxicity occurs. Finally, the route of drug administration may significantly alter the metabolism of a drug because it affects the organs to which the drug is exposed. This is most obvious when comparing oral with intravenous administration. Drugs given by mouth are potentially exposed to significant phase I metabolism in the small bowel mucosal cells and liver before entering the systemic circulation. SM CPT How are drugs excreted from the body? After oral administration, most drugs are absorbed across the small bowel SM CPT mucosa, enter the portal circulation and, if they survive first-pass metabolism, enter the systemic circulation. A proportion of the oral dose may not be absorbed at all because of its physicochemical properties or binding to food and is excreted in the faeces. After entering the systemic circulation, the parent drug and any metabolites are perfused through all of body tissues. There are multiple potential sites of excretion from the body. The most important site is the kidney which is primarily responsible for the excretion of low molecular weight compounds into the urine either as a result of glomerular filtration or active secretion into the renal tubules. The bile is responsible for excreting large molecular weight compounds (above 400–500 Da) into the bile which subsequently leave the body in the faeces. The lungs allow some volatile anaesthetic gases and small amounts of other compounds such as ethanol to leave the body in exhaled gases. Other routes of excretion for a small number of drugs are the tears, sweat,  in overall elimination they do offer the potential for detecting the presence of therapeutic and illicit drugs in the body. Breast milk is an important site of drug excretion for small amounts of many lipid-soluble drugs, which may be ingested by the infant. This does not represent an important route of excretion for the mother but the pharmacological effects of a small number of drugs can have important consequences for the infant (e.g. opioid analgesics, benzodiazepines). For any drug, or drug metabolite, to be excreted from the body, by any route, SM CPT it must be water-soluble. This is best illustrated by considering the excretion of drugs in the urine. Low-molecular-weight drugs are filtered into the renal tubules at the glomeruli. As the filtrate passes down the renal tubule, sodium and chloride ions along with water, are reabsorbed leaving behind an increasingly concentrated fluid to eventually become urine. As the fluid becomes more concentrated, the filtered molecules are subject to an increasing concentration gradient that favours their reabsorption back into the body. Those substances, including drugs, that are lipid-soluble, will rapidly diffuse back into the body down a concentration gradient. It is only the water- soluble molecules that are trapped in the tubular fluid, unable to diffuse across cell membranes back into the body, that will eventually be excreted.  The excretion of drugs in the urine depends on a combination of three SM CPT processes: Glomerular filtration carries water, ions and most molecules of low molecular mass across the fenestrated glomerular membrane into the renal tubule. The extent that drugs or their metabolites are filtered depends on renal blood flow and the degree of binding to plasma proteins. Only non- bound drug molecules are free to be filtered into the tubular fluid. It should be noted that filtration does not depend on lipid- or water-solubility because all low-molecular-weight compounds can cross the glomerular filtration membrane, irrespective of their polarity. Tubular secretion makes a further contribution to the amount of drug that enters the tubular fluid and does not depend on lipid-solubility or plasma protein binding. The tubular cells contain specialised transporter molecules that enable the active transport of acidic and basic drugs into the tubular lumen. Drugs using the same transporter may interact by competing for binding and excretion. For example, the drug probenecid has been used to compete with and decrease the active excretion of the antibiotic penicillin. Passive tubular reabsorption has a very important influence that reduces the excretion of many drugs and metabolites if they are sufficiently lipid- soluble to diffuse from the tubular fluid down their concentration gradient back into the body. For most molecules, the factor that determines their lipid-solubility is their degree of ionisation. Strongly acidic and strongly basic drugs remain in ionised form and water-soluble at any pH of urine and hence are excreted in the urine. Weakly acidic drugs such as salicylates and barbiturates are unionised in acidic urine and so they are reabsorbed into the circulation. The excretion of these weakly acidic drugs can be actively increased by making the urine more alkaline by the administration of  sodium bicarbonate, a procedure routinely employed after a severe salicylate overdose. Conversely, weakly basic drugs like morphine and amphetamine were also unionised and reabsorbed, but excretion can be increased if the urine is made acidic (e.g. with ascorbic acid). It is evident that renal excretion of drugs and their metabolites will be reduced if renal function (especially glomerular filtration) is impaired as a result of age, dehydration, the effects of other drugs or renal disease. When this happens, Bile is an important route of excretion for some drugs and their metabolites. SM CPT Biliary excretion Large molecular weight (>300 ENTEROHEPATIC CIRCULATION The factors that determine elimination via the biliary tract include Da) drugs Conjugated metabolites (e.g. Drugs or their metabolites that are sufficiently lipid- characteristics of the drug such as its chemical structure, polarity and soluble may be reabsorbed molecular size as well as characteristics of the liver such as the presence of glucuronides) after biliary secretion Active transport into bill Intestinal bacteria may cannaliculi against a specific active transport sites within the liver cell membranes. Drugs that are hydrolyse conjugated concentration gradient metabolites to enable this Specialised transport The circulation significantly most likely to be eliminated in the bile are larger molecules with a molecular molecules (e.g. P- increased the bioavailability glycoprotein) of some drugs Potential for saturation of Important examples include transport and competition between drugs oestrogens, thyroxine, cimetidine and methotrexate weight of greater than 300 Da and a degree of polarity. Smaller molecules are generally excreted only in negligible amounts. Conjugation, particularly with glucuronic acid, facilitates biliary excretion. Most of the drugs that are excreted into the bile cannaliculi require active transport against a concentration gradient. This involves specialised ATP- dependent transport proteins expressed on the canalicular membrane. These proteins are members of the ABC superfamily of transporters, and they mediate unidirectional transport of substrates (hepatic cytosol → bile) uphill against a large concentration gradient. Another important transporter is the multi-drug resistance protein, often referred to as P-glycoprotein. These transporters may become saturated and are potential sites of competition disease states, in which normal bile flow is reduced, will reduce drug elimination by this route, potentially resulting in drug toxicity. Examples of drugs that are excreted in bile include amiodarone, diazepam, digoxin, erythromycin, estradiol, lorazepam, morphine, sodium valproate and warfarin. Drugs that have been excreted in the bile enter the small bowel via the biliary tree. If they remain sufficiently lipid-soluble they may be reabsorbed in the small bowel and carried back to the liver via the portal venous system. They may then be re-excreted into the bile or re-enter the systemic circulation. This recycling between the liver, bile, gut and portal vein is known as the entero- hepatic circulation and may significantly reduce the rate at which some drugs are eliminated from the body. Therefore, biliary excretion eliminates substances from the body only to the extent that enterohepatic cycling is incomplete, that is, when some of the secreted drug is not reabsorbed from the intestine. The entero-hepatic circulation of drugs may be an important factor in maintaining their concentration and prolonging their residence and pharmacological effects in the body. Important examples include oestrogens, thyroxine, cimetidine, opioids, digoxin and warfarin. The recycling of glucuronide conjugates needs the presence of bacterial flora that have enzymes capable of hydrolysing the conjugated molecule, releasing the more lipid-soluble drug or active Phase I metabolite for reabsorption. Drugs that inactivate or kill micro-organisms (e.g. broad-spectrum antibiotics) can reduce reabsorption and drug availability. SM CPT What is the relationship between drug concentration and time (single dose)? First-order kinetics, sometimes known as ‘exponential’ SM CPT First-order (exponential) kinetics Law of mass action kinetics, is based on the law of mass action. The law of mass action proposes that the rate of a chemical reaction Drug Drug concentration Glomerular filtration Cytochrome P450 enzyme or process is directly proportional to the concentrations of Metabolite CYTOCHROME P450 SYSTEM the reactants. With regard to pharmacokinetics, this Metabolism Excretion implies that the rate of metabolism of drugs in the cytochrome P450 system in the liver will be proportional to their concentration. Similarly, the amount of drug excreted by glomerular filtration will be proportional to the concentration of the drug in the plasma.  For most drugs, the process of drug elimination, whether by metabolism or SM CPT excretion, is a high capacity process that does not become limited or saturated, even at high doses beyond the normal therapeutic range. Within this range, the rate of elimination is proportional to the amount of drug in the body (i.e. the higher the drug concentration the faster the rate of elimination). This is a logical consequence of the law of mass action because higher molecular concentrations will drive faster metabolic reactions or support higher renal filtration. This results in so-called first-order kinetics where a constant fraction of the drug remaining in the body is eliminated in a given time. In these circumstances, the decline in amount of drug in the body, or concentration of the drug in plasma, can be described mathematically by an exponential equation that is determined by the elimination rate constant, k. The exponential kinetics mean that there is a predictable decline in the fraction of the drug in the body, or its plasma concentration, over time. The fraction that is usually quoted is 50% and is known as the half-life. Wherever a sample is taken on the concentration-time curve, after one half-life, the plasma concentration will have halved. The importance of this relationship to prescribers is that it means that the SM CPT CP effect of increasing doses on plasma concentration is predictable. If a dose is doubled or trebled then this will lead to a doubled or trebled plasma concentration at all time points after dosing. Nevertheless, the elimination of each dose takes the same length of time. At all time points on each graph the time taken for the plasma concentration to halve (half-life, t½) remains constant for this drug. Note that this does not necessarily mean that the effect of the drug will double because that will also depend on the concentration- response relationship. Fortunately for prescribers, most drugs follow first-  order kinetics at therapeutic concentrations. For most drugs given in therapeutic doses, elimination is a first-order process, SM CPT in which there is no limit to the capacity of the processes of metabolism and excretion as the dose and plasma concentration increase. However, for some drugs, especially if given at higher toxic doses, the availability of the metabolising enzymes may be exceeded. When this happens, the rate of elimination will remain constant even if the dose increases, a situation that is described mathematically as zero-order or saturation kinetics. In these circumstances, the concentration-time graph forms a straight line. The presence of zero-order kinetics has important implications for prescribers. It means that the effect of dose titration becomes highly unpredictable. The rate of elimination fails to increase with increasing drug dose. Therefore, although a doubled or trebled dose results in twice or three times the initial plasma concentration, these proportionate increases in plasma concentration are no longer true at other times after dosing and may be several fold higher. The overall exposure to the drug, indicated by the area under the curve (AUC) may increase very significantly as the dosage rises with the risk of severe toxicity. The concept of half-life is no longer relevant because the time taken  point that is being considered. Important examples of drugs that are subject to zero-order metabolism are phenytoin, aspirin, paracetamol in overdose and ethanol. A particular concern when using drugs subject to zero-order metabolism is that if the drug is administered regularly at a rate faster than its maximum elimination rate then it will progressively accumulate to cause toxicity. The figure illustrates the concentration-time relationship after a single oral SM CPT dose of a drug that is eliminated by first-order kinetics. The plasma concentration rises as the drug enters and is absorbed from the small bowel reaching a peak (Cmax) after a delay (tmax) when the rate of absorption is equal to the rate of elimination. A subsequent exponential decline follows until the drug is completely eliminated. The area under the curve (AUC) is a function of the extent of absorption and represents the overall systemic exposure of the drug. In this example, the curve has been superimposed on the range spanning plasma concentrations between those that are just sufficient to produce the desired therapeutic effect - the minimum effective concentration (MEC) - and the plasma concentration beyond which concentration-related adverse events are intolerable - the maximum tolerated concentration (MTC). It can be seen that there is a delay to the onset of therapeutic effect while the plasma concentration rises into the therapeutic range and the necessary concentration is only maintained for a limited time - the duration of action - before the plasma concentration falls to sub-therapeutic levels. If continuous  need to be given to maintain the plasma concentration in the therapeutic range. It is important to recognise that this illustrative plot relates to the administration of a drug to a single theoretical patient. There will be some variation between patients in the rate and extent of absorption, the peak plasma concentration achieved, the rate of elimination and the plasma concentration associated with therapeutic or adverse effects. This diagram shows similar concentration-time relationship but for a drug with SM CPT a narrower therapeutic range (sometimes described as a low therapeutic index). In this circumstance, the peak plasma concentration is higher than the maximum tolerated concentration and so there will be a period shortly after administration when there is a high probability that the patient will experience adverse effects. Although this situation could be rectified by lowering the dose, this would have the disadvantage that the plasma concentration would be sub-therapeutic for a longer period of time, necessitating more frequent repeated doses. A good example in therapeutics is the use of calcium channel blocking drugs for the treatment of hypertension (e.g. nifedipine, verapamil). These drugs are vasodilators and patients often suffer the predictable adverse effects of vasodilatation shortly after administration such as headache, flushing and dizziness. To address these problems, and avoid the need for more frequent administration, manufacturers have developed so-called modified-release (m/ r) versions of these medicines. These formulations are designed to delay the release of the drug in the small bowel so that absorption occurs over a much  provides a much smoother increase and slower subsequent decline in plasma concentration, allowing the effects of drugs with short half-lives to be prolonged. Such formulations may also be referred to as ‘controlled release (CR)’, ‘slow release (SR)’ or ‘long acting (LA)’ formulations. SM CPT What is the relationship between drug concentration and time (repeated doses)? When doses are repeated, the second and subsequent doses are given at a SM CPT time when the previous doses have not been completely eliminated. This means that the drug will progressively accumulate in the body and its eventual plasma concentration will be considerably higher than that after a single dose. Accumulation will continue until a steady state is reached because the rate of elimination of the drug is equal to the rate of administration. After regular dose administration begins, the peak, average and trough  is reached when the concentration of drug in the body is sufficient to mean that the rate of elimination is equal to the rate of drug absorption. The rate at which the plasma drug concentration increases, and time taken to achieve steady state, are determined by the drug half-life. After one half-life, 50% of steady state is achieved, after two half-lives 75% and so on. By convention, it is generally considered that, for practical purposes, steady state is achieved after 5 half-lives. In other words, it requires 5 half-lives before the impact of a particular dosing regimen can be properly judged. In the example shown, the half-life and the dosing interval are the same and it might be tempting to believe that it is 5 doses, rather than 5 half-lives, that allow steady state to be achieved. However, the importance of half-life can be demonstrated by considering a drug with a much shorter half-life that is also dosed at 12 hour intervals. If the half-life was a mere 2 hours, then almost all of the initial dose would have been eliminated by the time the second dose was administered 12 hours later. In other words, steady state would already exist by the time of the second dose. When the general properties of long and short half-life drugs are compared it SM CPT Long versus short half-life drugs can be seen that there are advantage and disadvantages of each. Long half-life drugs take longer to eliminate, which may be seen as an LONG HALF-LIFE Less frequent (once daily) dosing SHORT HALF-LIFE Rapid steady-state after initiation or dose titration advantage because it means less frequent dosing, better adherence to the Improved adherence Slow to reach steady-state Fine control of pharmacological effect Frequent dosing required (reduces adherence) dosing regimen by patients and a higher chance that the drug concentration will remain in the therapeutic range by the time of trough prior to the next Loading dose may be needed May not be suitable for oral administration Slow to be eliminated Wide spread between peak and trough Examples: digoxin (36 h), atenolol (8 h), Examples: nifedipine (2 h), levodopa (2 h), amiodarone (500 h) amoxicillin (1 h), dobutamine (2 mins) dose. On the other hand, the longer half-life also means that it takes longer to  loading doses may be required if swift onset of action is required and washout takes longer after discontinuation because of the emergence of adverse effects. Examples include the beta-adrenoceptor blocker atenolol, the cardiac glycoside digoxin and the anti-arrhythmic drug amiodarone. Short half-life drugs are eliminated quickly, which may be seen as an advantage if rapid fine control of plasma concentration and pharmacological effect are required. On the other hand, the short half-life also means that more regular dosing is required and the variation between peak and trough concentrations may be wide with the inherent risk that peaks may cause adverse effects while troughs are associated with loss of therapeutic effect. Examples of drugs with shorter half-lives include standard formulations of calcium channel blockers used to treat hypertension, levodopa used to treat Parkinson’s disease and some antibiotics used to treat infections.bIn fact, drugs with very short half-lives have to be given by continuous infusion or inhalation for the pharmacological effect to be maintained. Examples are vasoactive drugs used on intensive care units (e.g. dobutamine) and volatile anaesthetic drugs (e.g. halothane). Several factors will determine the optimal dosing regimen for individual drugs. SM CPT For those individual drugs it is their half-life that will determine their dosing characteristics. The half-life will influence how quickly steady state is achieved after the drug is started or the dose is altered, how quickly the drug is eliminated after intermittent dosing and, therefore, how quickly the plasma concentration falls, and the range between peak and trough plasma concentration. drug concentrations. Some drugs need to produce a continuous pharmacological effect to achieve clinical benefit. This may be over a relatively short duration (e.g. vasoconstrictor drugs in patients with shock on an intensive care unit) or a prolonged period (e.g. the use of antihypertensive drugs to control blood pressure and prevent strokes). Stable concentrations are less important for other drugs (e.g. bactericidal antibiotics that may need to be at sufficient concentration only briefly after each dose). The risks associated with excessive peak plasma concentrations may also be a relevant factor. When drugs are administered intermittently the plasma concentration fluctuates between peaks and troughs. With larger dose intervals although the average concentration is the same (assuming the overall rate of administration is the same), the peaks are higher and the troughs are lower. This matters if the peaks cause serious adverse effects. Prescribers also need to consider how important it is to achieve effective drug concentrations rapidly. Some drugs need to produce their pharmacological effects rapidly because of the importance of the clinical circumstances (e.g. anti-arrhythmic drugs such as digoxin in patients with rapid trial fibrillation, the antibiotic benzylpenicillin in patients with meningococcal meningitis). This is a problem for drugs have long half-lives, which take a long time to reach steady state concentrations.  Long half-life drugs, such as the cardiac glycoside digoxin (t½ = 36 hours) will SM CPT not reach steady state concentration for about a week after starting treatment. This is a problem because, during much of the period of accumulation towards a safe and effective steady state plasma concentration, the concentration of digoxin will be insufficient to yield the necessary pharmacological effect of reducing the rapid heart beat of atrial fibrillation. Giving larger or more frequent doses might achieve an effective concentration sooner but the concentration will continue to rise beyond this, leading to adverse effects at steady state. For drugs with long half-lives, the only way to achieve a target plasma concentration safely before five half-lives have elapsed is to give an initial loading dose that is much larger than the regular maintenance dose, and equivalent to the amount of drug required in the body at steady state. This achieves an immediate peak plasma concentration close to the steady state concentration, which can then be maintained by successive maintenance doses. This summary diagram highlights how the four phases of pharmacokinetics SM CPT mean in practice for drug handling in the body. It shows the three main compartments into which drugs might distribute - the circulating plasma, the rather larger volume of interstitial fluid surrounding the cells of all body tissues and, the largest compartment, the intracellular fluid and fat. The plasma is constantly circulating through two organs with a rich blood supply that are very influential upon the pharmacokinetic handling of drugs: (i) the liver, where many drugs are metabolised, and (ii) the kidney, where many drugs and their metabolites are excreted, if they are sufficiently water-soluble. Most drugs are taken orally and enter the body via the oesophagus and stomach. If the drug is capable of surviving gastric acid and avoids unacceptable binding by food, it becomes available for absorption across the small bowel mucosa. In order to be absorbed across the mucosa the drug must have sufficient lipid solubility and avoid metabolism by the many enzymes within it. Unabsorbed and metabolised drug will be excreted in the faeces. Absorbed drug molecules subsequently enter the portal circulation from where they are carried to the liver. The liver is a very rich source of drug metabolising enzymes and a proportion of the ingested dose may be metabolised there and never reach the circulation, a process known as first- pass metabolism. Those passing through unchanged enter the systemic circulation, from which they may diffuse out into the interstitial fluid surrounding most body tissues and from there into the intracellular fluid and fat. This distribution process will continue until an equilibrium is reached in the concentration between each compartment. As soon as any drug molecules are circulating in the plasma, they will be continuously re-exposed to the metabolising enzymes in the liver. The resulting metabolites, as well as native drug molecules, will also be continuously available for potential for excretion in the urine or bile. As the plasma drug concentration falls because of metabolism and excretion, drug that was distributed towards the tissues begins to re-equilibrate back towards the plasma. This process will eventually lead to the removal of all of the drug with time (inset graph) unless further doses are administered. First-pass metabolism, and all of the other uncertainties inherent following  or rectal mucosa, or injected parenterally by intravenous, intramuscular or subcutaneous injection. Drugs that are injected are completely absorbed into the circulation without loss. SM CPT Key points Pharmacokinetics may be thought of as ‘what the body does to a drug’ The four aspects of pharmacokinetics - absorption, distribution, metabolism and excretion - collectively determine the time course of drug action The rate and extent of a drug’s absorption depend on the route by which it is given and its physicochemical characteristics Drugs that have been absorbed are then distributed through body compartments based on molecular size and lipid-solubility Drug metabolism occurs chiefly in the liver and its purpose is to (i) deactivate the drug and (ii) change the chemical nature of the drug so that it is sufficiently water-soluble to be excreted in the urine or bile An understanding of pharmacokinetics is important for prescribers because it accounts for most of the individual variation in drug response and often explains why some prescriptions result in suboptimal or excessive effects SM CPT Key points Given by any route other than intravenously, the absorption of a drug is dependent on its physicochemical properties (molecular weight, lipid solubility, chemical nature) and its pharmaceutical form The rate of absorption across a membrane is determined by its surface area and the concentration gradient between the two sides, maintained by removal into the circulation Rate of absorption of drugs with low lipid solubility is limited by the rate of membrane penetration but highly lipid-soluble drugs cross membranes so rapidly that it is limited primarily by tissue perfusion For most drugs administered in tablet form, the rate of drug absorption is limited by how long it takes for the drug to enter solution, which depends on the rate of disintegration and dissolution of the tablet, and the aqueous solubility of the drug The cells of the small bowel wall contain a large number of enzymes capable of metabolising drug molecules passing through them, but because of its greater enzyme content, most ‘first- pass’ metabolism of drugs given orally occurs during passage through the liver cells Drugs can affect each others’ absorption after an oral dose by interacting in the gut lumen, altering the rate of gastric emptying or changing the rate of first-pass metabolism, and after intramuscular injection by altering blood flow to the injection site SM CPT Key points Drugs that have been absorbed into the body distribute between plasma, other extracellular fluids and intracellular fluid Many drugs bind to plasma proteins as a drug–protein complex, which confines them to the plasma until the complex dissociates and this binding slows the process of drug distribution and delays elimination Drugs disperse from the plasma to the tissues by various processes, including filtration, diffusion (aqueous, simple, facilitated), active transport and pinocytosis The apparent volume of distribution is the volume of fluid required to contain the total amount of drug in the body at the same concentration as that in plasma and is estimated by measuring the plasma drug concentration shortly after dosing The volume of distribution is the volume that must be cleared of the drug before elimination is complete and, along with the rate of clearance, is one of the two determinants of half-life SM CPT Key points Drug metabolism serves to inactivate pharmacologically active molecules and then convert them into a water-soluble form that can be excreted in the urine or bile The liver is the main site of drug metabolism in the body but other important sites are the small bowel (which may inactivate drugs before they can be absorbed), the kidneys and the skin Phase I metabolism involves oxidation, reduction or hydrolysis reactions catalysed by the cytochrome P450 enzyme superfamily found in the smooth endoplasmic reticulum of the liver Phase II metabolism involves conjugation reactions with glucuronide, sulfate or acetyl groups that make a drug, or its phase I metabolite, more water-soluble Factors that influence the rate of drug metabolism include genetics, age, sex, nutritional status, the presence of disease, interacting drugs, drug dose and the route of administration Liver metabolism is a common site of drug interactions as one drug interferes with the clearance of another because it either induces the formation of more metabolising enzymes or competes for and inhibits metabolism The loss of a proportion of an orally administered drug dose by metabolism in the small bowel mucosa and liver is known as first-pass metabolism and can significantly reduce the bioavailability of some drugs SM CPT Key points The major routes of excretion of drugs and their metabolites from the body are the urine, the bile and the faeces although some drugs can be excreted and detected elsewhere (e.g. exhaled breath, sweat, saliva, tears, breast milk) The kidney excretes low molecular weight molecules that can be filtered at the glomerulus but they must be sufficiently water-soluble to avoid passive diffusion back into the body in the renal tubules Drugs that are excreted in the bile are usually high molecular weight molecules including conjugated drug metabolites, which may be reabsorbed back into the portal circulation and return to the liver in a process known as enterohepatic circulation. The rate of elimination of drugs from the body is a composite of their metabolism and excretion at all sites and is higher at high plasma concentration Clearance is the rate of elimination divided by the plasma concentration and expresses the volume that is completely cleared of a drug over a given time - it is independent of plasma drug concentration SM CPT Key points The pharmacokinetic handling of a drug can be described by plotting its plasma concentration against time after a single dose The majority of drugs are eliminated by first-order kinetics where the rate of elimination is directly proportional to the plasma concentration Half-life describes the time period over which the plasma concentration halves A small number of drugs are eliminated by zero-order kinetics where the rate of elimination is constant - this is important because the change in plasma concentration following a dose change is unpredictable The concentration-time curve affects the period of time during which the plasma concentration is sufficient to provide beneficial effects or reaches concentrations that cause adverse effects SM CPT Key points Most drugs must be administered regularly to sustain their pharmacological effects Following regular intermittent doses, the plasma drug concentration rises gradually to reach a steady state after around 5 half-lives when the rate of administration is equal to the rate of elimination (by metabolism and excretion) At steady state, there is a fluctuation between peak plasma concentration shortly after dosing and trough concentration just before the next dose is administered - these fluctuations are important because the peak may be associated with adverse effects and the trough with ineffectiveness The fluctuation between peak and trough can be minimised by more frequent dosing but this strategy is inconvenient for patients and may be associated with non-adherence - this problem can be overcome by the development of modified-release formulations When drugs are administered continuously by intravenous infusion, the plasma concentration rises smoothly (without peaks and troughs) to achieve a steady state after 5 half-lives For drugs with long half-lives, the delay before therapeutic concentrations are achieved can be overcome by giving an initial loading dose followed by smaller maintenance doses You can find further reading and resources to support your learning at the SM CPT Further reading Ritter JM, Flower RJ, Henderson G, Loke YK, MacEwan D, Rang locations listed. HP. Pharmacology. London: Elsevier, 2020 (9th Edition). Chapter 9. Absorption and distribution of drugs. Chapter 10. Drug metabolism and elimination. Buxton ILO. In Goodman & Gilman’s the pharmacological basis of therapeutics (13th Ed). Chapter 2. Pharmacokinetics. New York: McGraw Hill Press, 2018. Maxwell SRJ. Clinical therapeutics and good prescribing (Chapter 2). In Davidson's Principles and Practice of Medicine 2018; pp 13–36. Clinical Pharmacology Online channel. https://vimeo.com/ channels/1320434 Pharmacokinetics (7 short videos)