Pharmacokinetics: Metabolism And Excretion Of Drugs, Kinetics Of Elimination PDF

Pharmacokinetics: Metabolism Chapter 3 and Excretion of Drugs, Kinetics of Elimination BIOTRANSFORMATION (iii) Activation of inactive drug Few drugs (Metabolism) are inactive as such a...

Pharmacokinetics: Metabolism Chapter 3 and Excretion of Drugs, Kinetics of Elimination BIOTRANSFORMATION (iii) Activation of inactive drug Few drugs (Metabolism) are inactive as such and need conversion in the body to one or more active metabolites. Such a Biotransformation means chemical alteration drug is called a prodrug (see box). The prodrug of the drug in the body. It is needed to ren­ may offer advantages over the active form in der nonpolar (lipid-soluble) compounds polar being more stable, av·ng better bioavailability (lipid-insoluble) so that they are not reabsorbed or other desfrable pha macokinetic properties or in the renal tubules and are excreted. In the less side effects and toxicity. Some prodrugs absence of metabolism, body will not be able are activated selectively at the site of action. to get rid of lipophylic substances, and they will become very long acting. Most hydro­ tiffiMW' ·Ah941114ri®Gi· philic drugs, e.g. streptomycin, neostigmine, Mor12hine Morphine-6-glucuronide pancuronium, etc. are little biotransformed and Ce otaxime Desacetyl cefotaxime are largely excreted unchanged. Mechanisms.A:llopurinol Alloxanthine which metabolize drugs (essentially fo gn Rrocainamide N-acetyl procainamide substances or Xenobiotics) have developed Primidone Phenobarbitone, phenylethylmalonamide to protect the body from ingested toxin an Diazepam Desmethyl-diazepam, other environmental chemicals. oxazepam The primary site for drug metabolism is Digitoxin Digoxin liver; others are-kidney, intestine, lungs and lmipramine Desipramine plasma. Biotransformation of drugs may lead Amitriptyline Nortriptyline to the following. Codeine Morphine Spironolactone Canrenone (i) Inactivation Most drugs and their active Losartan E 3174 metabolites are rendered inactive or less active, e.g. ibuprofen, paracetamol, lidocaine, chloramp­ Biotransformation reactions can be classified into: henicol, propranolol and its active metabolite (a) Nonsynthetic/Phasel/Functionalization reac­ 4-hydroxypropranolol. Thus, biotransformation tions: a functional group (-OH, -COOH, -CHO, provides an alternative method of terminating -NH2 , -SH) is generated or exposed-metabolite drug action to excretion. may be active or inactive. (ii) Active metabolite from an active drug (b) Synthetic/Conjugation/ Phase II reactions: Many drugs have been found to be partially an endogenous radical is conjugated to the converted to one or more active metabolite; the drug-metabolite is mostly inactive; except few effects observed are the sumtotal of that due drugs, e.g. glucuronide conjugate of morphine to the parent drug and its active metabolite(s) and sulfate conjugate of minoxidil are active. (see box). Certain drugs already have functional groups and  Metabolism and Excretion of Drugs, kinetics of elimination 29 are directly conjugated, while others undergo a Depending upon the extent of amino acid sequence phase I reaction first followed by a phase II homology, the cytochrome P-450 (CYP) isoenzymes are grouped into families designated by numerals (1, 2, 3.....), reaction (see Fig. 3.1). each having several sub-families designated by capital let- ters (A, B, C.....), while individual isoenzymes are again Prodrug Active form alloted numerals (1, 2, 3....). In human beings, only a Levodopa — Dopamine few members of three isoenzyme families (CYP 1, 2 Enalapril — Enalaprilat and 3) carryout metabolism of most of the drugs, and a-Methyldopa — a-methylnorepinephrine many drugs such as tolbutamide, barbiturates, phenytoin, Dipivefrine — Epinephrine paracetamol are substrates for more than one isoform. The Proguanil — Cycloguanil CYP isoenzymes important in man are: Prednisone — Prednisolone CYP3A4/5 Carryout biotransformation of largest num- Clopidogrel — Thiol metabolite ber (nearly 50%) of drugs. In addition to liver, these Bacampicillin — Ampicillin isoforms are expressed in intestine (responsible for first Sulfasalazine — 5-Aminosalicylic acid pass metabolism at this site) and kidney as well. Inhibi- Cyclophos- — Aldophosphamide, tion of this isoenzyme by erythromycin, clarithromycin, phamide phosphoramide mustard, ketocona­zole, itraconazole is responsible for the important acrolein drug interaction with terfenadine, astemizole and cisapride Fluorouracil — Fluorouridine (see p. 181) which are its substrates. Verapamil, ritonavir monophosphate and a constituent of grape fruit juice are other important Mercaptopurine — Methylmercaptopurine inhibitors. CHAPTER 3 ribonucleotide CYP2D6 This is the next most important CYP isoform Acyclovir — Acyclovir triphosphate which metabolizes nearly 20% drugs including tricyclic antidepres­sants, selective serotonin reuptake inhibitors, many neuro­leptics, antiarrhythmics, codeine, debrisoquine, Nonsynthetic reactions metoprolol. Inhibition of this enzyme by quinidine results in (i) Oxidation This reaction involves addition failure of conversion of codeine to morphine → analgesic effect of codeine is lost. Human subjects can be grouped of oxygen/negatively charged radical or removal into ‘extensive’ or ‘poor’ metabolizers of metoprolol and of hydrogen/positively charged radical. Oxida­ debrisoquin. The poor metabolizers have an altered CYP2D6 tions are the most important drug metabolizing enzyme and exhibit low capacity to hydroxylate many reac­tions. Various oxidation reactions are: drugs. An ultrarapid metabolizer genotype of CYP2D6 hydroxylation; oxygenation at C, N or S has also been identified. atoms; N or O-dealkylation, oxidative deami­ CYP2C8/9 Important in the biotransformation of >15 nation, etc. commonly used drugs including phenytoin, carbamazepine, In many cases the initial insertion of oxygen warfarin which are narrow safety margin drugs. atom into the drug molecule produces short CYP2C19 Metabolizes > 12 frequently used drugs including lived highly reactive quinone/epoxide/superox- omeprazole, lansoprazole, phenytoin, diazepam. Omeprazole ide intermediates which then convert to more and fluconazole are its inhibitors. stable compounds. CYP1A1/2 Though this subfamily participates in the Oxidative reactions are mostly carried out meta­bolism of only few drugs like theophylline, caffeine, paraceta­m ol, carbamazepine, it is more important for by a group of monooxygenases in the liver, activation of procarcinogens. Polycyclic hydrocarbons, which in the final step involve a cytochrome cigarette smoke and charbroiled meat are its potent P-450 haemo­­protein, NADPH, cytochrome P-450 inducers. reductase and molecular O2. More than 100 CYP2E1 It catalyses oxidation of alcohol, holothane, and cytochrome P-450 (CYP) iso­enzymes differing formation of minor metabolites of few drugs, notably the in their affinity for various substrates (drugs), hepatotoxic N-acetyl benzo­quinoneimine from paracetamol; have been identified. The CYP isoenzymes im- chronic alcoholism induces this isoenzyme. portant for drug metabolism in humans, along The relative amount of different cytochrome with their clinically relevant substrate drugs, P-450s differs among species and among indi- inhibitors and inducers are listed in Table 3.1 viduals of the same species. These differences  30 GENERAL PHARMACOLOGY Table 3.1: Major drug metabolizing CYP450 isoenzymes in humans with their important substrate drugs, inhibitors and inducers CYP-450 isoenzyme Drugs metabolized Inhibitors Inducers CYP3A4 Terfenadine, Astemizole Erythromycin Barbiturates CYP3A5 Cisapride, Losartan Clarithromycin Phenytoin Carbamazepine, Hydrocortisone Ketoconazole Carbamazepine Paracetamol, Diazepam Itraconazole Rifampin Buspirone, Mifepristone Verapamil Glucocorticoids Ritonavir, saquinavir Ritonavir Nevirapine Simvastatin, Quinidine Fluoxetine Verapamil, Lidocaine Grape fruit juice Dapsone, Nevirapine CYP2D6 Metoprolol, Debrisoquine Qunidine Phenobarbitone Nebivolol, Amitryptyline Fluoxetine Rifampin Clomipramine, Fluoxetine Paroxetine Paroxetine, Venlafaxine Haloperidol, Clozapine Risperidone, Codeine Propafenone, Flecainide CYP2C8 Phenytoin, Carbamazepine Fluvoxamine Phenobarbitone SECTION 1 CYP2C9 Warfarin, Tolbutamide Fluconazole Carbamazepine Repaglinide, Pioglitazone Gemfibrozil Rifampin Diclofenac, Ibuprofem Trimethoprim Losartan CYP2C19 Omeprazole, Lansoprazole Omeprazole Carbamazepine Amitriptyline, Citalopram Fluconazole Rifampin Phenytoin, Diazepam Propranolol, Clopidogrel CYP1A1 Theophylline, Caffeine Fluvoxamine Polycyclic hydrocarbons CYP1A2 Paracetamol, Warfarin Fluoxetine Cigarette smoke Carbamazepine Charbroiled meat Rifampin Carbamazepine CYP2E1 Alcohol, Halothane Disulfiram Chronic alcoholism Paracetamol* Fomepizole Isoniazid CYP2B6 Efavirenz, Nevirapine Paroxetine phenobarbitone Cyclophosphamide, Methadone Sertraline Cyclophosphamide Sertraline, Clopidogrel Clopidogrel * Generates toxic metabolite n-acetyl-p-benzoquinoneimine (NABQI) largely account for the marked interspecies and that are also located on hepatic endoplasmic interindividual differences in rate of metabolism reticulum, but are distinct from CYP enzymes. of drugs. these enzymes are not susceptible to induc- Barbiturates, phenothiazines, imipramine, tion or inhibition by other drugs, and thus are propranolol, ibuprofen, paracetamol, steroids, not involved in drug interactions. Some other phenytoin, benzodiazepines, theophyl­ line and drugs, e.g. adrenaline, alcohol, mercaptopurine many other drugs are oxidized in this way by are oxidized by mitochondrial or cytoplasmic CYP450. In addition few drugs like cimetidine, enzymes. ranitidine, clozapine are oxidized at their N, P or (ii) Reduction This reaction is the converse S atoms by a group of flavin-monooxygenases of oxidation and involves cytochrome P-450  Metabolism and Excretion of Drugs, kinetics of elimination 31 enzymes working in the opposite direction. pathway. Glucuronidation increases the molecular Alcohols, aldehydes, quinones are reduced. Drugs weight of the drug which favours its excretion prima­rily reduced are chloralhydrate, chloramp­ in bile. Drug glucuronides excreted in bile he­nicol, halothane, warfarin. can be hydrolysed by bacteria in the gut—the (iii) Hydrolysis This is cleavage of drug liberated drug is reabsorbed and undergoes mole­cule by taking up a molecule of water. the same fate. This enterohepatic cycling (see Fig. 3.2) of the drug prolongs its action, e.g. esterase phenolphthalein, oral contra­ ceptives. Ester + H2O Acid + Alcohol (ii) Acetylation Compounds having amino Similarly, amides and polypeptides are hydro­ or hydra­zine residues are conjugated with the lysed by amidases and peptidases. In addition, help of acetyl coenzyme-A, e.g. sulfonamides, there are epoxide hydrolases which detoxify isonia­zid, PAS, dapsone, hydralazine, clonaz- epoxide metabolites of some drugs generated epam, procaina­ mide. Multiple genes control by CYP oxygenases. Hydrolysis occurs in liver, the N-acetyl transferases (NATs), and rate of intestines, plasma and other tissues. Examples acetylation shows genetic polymorphism (slow of hydrolysed drugs are choline esters, procaine, and fast acetyla­ tors). lidocaine, procaina­mide, aspirin, indomethacin, carbamazepine-epoxide, pethidine, oxytocin. (iii) Methylation The amines and phenols can CHAPTER 3 (iv) Cyclization This is formation of ring be methylated by methyl transferases (MT); struc­ture from a straight chain compound, e.g. methionine and cysteine acting as methyl cycloguanil from proguanil. donors, e.g. adrenaline, histamine, nico­tinic acid, methyldopa, captopril, mercaptopurine. (v) Decyclization This implies opening up of ring struc­ture of the cyclic drug molecule, such (iv) Sulfate conjugation The phenolic com­ as barbi­turates, phenytoin. This is generally a pounds and steroids are sulfated by sulfotrans­ minor pathway. ferases (SULTs), e.g. chloramphenicol, methyl­ dopa, adrenal and sex steroids. Synthetic reactions (v) Glycine conjugation Salicylates, nicotinic These reactions involve conjugation of the drug acid and other drugs having carboxylic acid or its phase I metabolite with an endogenous group are conju­gated with glycine, but this is substrate, usually derived from carbohydrate not a major pathway of metabolism. or amino acid, to form a polar highly ionized (vi) Glutathione conjugation This is carried organic acid, which is easily excreted in urine out by glutathione-S-transferase (GST) forming or bile. Conju­gation reactions have high energy a mercap­­­­tu­rate. It is normally a minor pathway. requirement and are generally faster than phase However, it serves to inactivate highly reactive I reactions. quinone or epoxide intermediates formed during (i) Glucuronide conjugation This is the most metabo­lism of certain drugs, e.g. paracetamol. important synthetic reaction carriedout by a When large amount of such intermediates are group of UDP-glucuronosyl transferases (UGTs). formed (in poisoning or after enzyme induction), Compounds with a hydroxyl or carboxylic acid gluta­thio­ne supply falls short—toxic adducts are for­med with tissue constituents resulting in group are easily conjugated with glucuronic acid hepatic, renal and other tissue damage. which is derived from glucose. Examples are— chloramphenicol, aspirin, paracetamol, diazepam, (vii) Ribonucleoside/nucleotide synthesis lorazepam, morphine, metronidazole. Not only This pathway is important for the activation drugs but endogenous substrates like bilirubin, of many purine and pyrimidine antimetabolites steroidal hormones and thyroxine utilize this used in cancer chemotherapy.  32 GENERAL PHARMACOLOGY as well as in other tissues including plasma. The esterases, amidases, some flavoprotein oxi- dases and most conju­gases are nonmicrosomal. Reactions catalysed are: Some oxidations and reductions, many hydro­­ lytic reactions and all conjugations except glucuronidation. The nonmicrosomal enzymes are not induc- ible but many show genetic polymorphism (acetyl Fig. 3.1: Simultaneous and/or sequential metabolism of trans­ferase, pseudocholinesterase) similar to the a drug by phase I and phase II reactions microsomal enzymes. Both microsomal and nonmicrosomal enzy­ mes are deficient in the newborn, especially Most drugs are metabolized by multiple premature, making them more susceptible to path­ways, simultaneously or sequentially as many drugs, e.g. chloramphenicol, opioids. This illus­trated in Fig. 3.1. Rates of reaction by deficit is made up in the first few months, different pathways often vary considerably. A more quickly in case of oxidation and other variety of metabolites (some more, some less) phase I reactions than in case of glucuronide SECTION 1 of a drug may be produced. Stereoisomers of and other conjugations which take 3 or more a drug may be metabolized differently and at months to reach adult levels. different rates, e.g. S-warfarin rapidly under- The amount and kind of drug metabolizing goes ring oxidation, while R-warfarin is slowly enzy­mes is controlled genetically and is also degraded by sidechain reduction. altered by diet, environmental factors. Thus, Only a few drugs are metabolized by enzymes marked inter­species and interindividual differ- of intermediary metabolism, e.g. alcohol by ences are seen, e.g. cats are deficient in UGTs dehy­dro­genase, allopurinol by xanthine oxidase, while dogs are deficient in NATs. Upto 6-fold succinylcholine and procaine by plasma choli­ difference in the rate of metabolism of a drug nes­­terase, adrenaline by monoamine oxidase. among normal human adults may be observed. Majority of drugs are acted on by relatively This is one of the major causes of individual nonspecific enzymes which are directed to types variation in drug response. of molecules rather than to specific drugs. The same enzyme can metabolize many drugs. The Hofmann elimination This refers to inactiva­ drug metabolising enzymes are divided into tion of the drug in the body fluids by spon­ two types: taneous molecular rearrangement without the agency of any enzyme, e.g. atracurium. Microsomal enzymes These are located on smooth endoplasmic reticulum (a system of Inhibition of Drug Metabolism microtubules inside the cell), primarily in liver, Azole antifungal drugs, macrolide antibiotics and also in kidney, intestinal mucosa and lungs. some other drugs bind to the heme iron in CYP450 The monooxyge­nases, cytochrome P450, UGTs, and inhibit the metabolism of many drugs, as epoxide hydrolases, etc. are microsomal enzymes. well as some endogenous substances like steroids, They catalyse most of the oxidations, reduc­ bilirubin. One drug can competitively inhibit the tions, hydrolysis and glucuronide conjugation. meta­bolism of another if it utilizes the same Microsomal enzymes are inducible by drugs, enzyme or cofactors. However, such interactions certain dietary constituents, and other agencies. are not as common as one would expect, because Nonmicrosomal enzymes These are present in often different drugs are substrates for different the cyto­plasm and mitochondria of hepatic cells CYP-450 isoenzymes. It is thus important to  Metabolism and Excretion of Drugs, kinetics of elimination 33 know the CYP isoenzyme(s) that carry out the (within hours) compared to enzyme induction metabolism of a particular drug. A drug may be (see below). the substrate as well as inhibitor of the same Metabolism of drugs with high hepatic Cyp isoenzyme. In case the drug inhibits its own extraction is dependent on liver blood flow metabolism, the oral bioavailability is likely to (blood flow limited metabolism). Proprano- increase (for high first pass metabolism drugs), lol reduces rate of lidocaine metabolism by while systemic clearance is likely to decrease, decreasing hepatic blood flow. Some other prolonging plasma half life. On chronic dosing, drugs whose rate of metabolism is limited by the oral bioavailability of verapamil is nearly hepatic blood flow are morphine, propranolol, doubled and t½ is prolonged, because it inhibits verapamil and imipra­mine. its own metabolism. A drug may also inhibit one isoenzyme while being itself a substrate of another Microsomal Enzyme Induction isoenzyme, e.g. quinidine is metabolized mainly Many drugs, insecticides and carcinogens by CYP3A4 but inhibits CYP2D6. Moreover, interact with DNA and increase the synthesis of majority of drugs, at therapeutic concentrations, microsomal enzyme protein, especially cytoch­ are metabolized by non-saturation kinetics, i.e. the rome P-450 and UGTs. As a result the rate of enzyme is present in excess. Clinically significant meta­bolism of inducing drug itself (autoinduc- inhibition of drug metabolism occurs in case of tion) and/or some other coadministered drugs CHAPTER 3 drugs having affinity for the same isoenzyme, is accelerated. specially if they are metabolized by saturation Different inducers are relatively selective for kinetics or if kinetics changes from first order to certain cytochrome P-450 isoenzyme families, zero order over the therapeutic range (capacity e.g.: limited metabolism). The ‘boosted’ HIV-protease Anticonvulsants (phenobarbitone, phenytoin, inhibitor (PI) strategy utilizes the potent CYP3A4 carbamazepine), rifampin, glucocorti­ coids inhibitory action of low dose ritonavir to lower induce CYP3A isoenzymes. the dose of other PIs like atazanavir, lopinavir, Phenobarbitone and rifampin also induce saquinavir given concurrently. Obviously, inhibition CYP2D6 and CYP2C8/9. of drug metabolism occurs in a dose related Carbamazepine and rifampin, in addition, manner and can precipitate toxicity of the object induce CYP2C19 and CYP1A1/2. drug (whose metabolism has been inhibited). Isoniazid and chronic alcohol consumption Because enzyme inhibition occurs by direct induce CYP2E1. effect on the enzyme, it has a fast time course Polycyclic hydrocarbons like 3-methylcholan­ threne and benzopyrene found in cigarette smoke, charcoalbroiled meat, omeprazole Drugs that inhibit drug metabolizing enzymes and industrial pollutants induce CYP1A Allopurinol Amiodarone iso­enzymes. Omeprazole Propoxyphene Other enzyme inducers are: chronic alcohol- Erythromycin Isoniazid ism, nevirapine, griseofulvin, DDT. Clarithromycin Cimetidine Since different CYP isoenzymes are Chloramphenicol Quinidine involved in the metabolism of different drugs, Ketoconazole Disulfiram every inducer increases biotransformation of Itraconazole Diltiazem certain drugs but not that of others. How- Metronidazole Verapamil ever, phenobarbitone like inducers of CYP3A Ciprofloxacin MAO inhibitors and CYP2D6 affect the metabolism of a Fluoxetine (and Ritonavir (and other large number of drugs, because these isoen- other SSRIs) HIV protease inhibitors) zymes act on many drugs. On the other hand  34 GENERAL PHARMACOLOGY induction by polycyclic hydrocarbons is lim- Possible uses of enzyme induction ited to few drugs (like theophylline, warfarin) 1. Congenital nonhaemolytic jaundice: It is because CYP1A isoenzyme metabolizes only due to deficient glucuronidation of bilirubin; few drugs. pheno­barbitone hastens clearance of jaundice. Induction involves microsomal enzymes in 2. Cushing’s syndrome: phenytoin may reduce liver as well as other organs and increases the the manifestations by enhancing degradation of rate of metabolism by 2–4 fold. Induction takes adrenal steroids which are produced in excess. 4–14 days to reach its peak and is maintained 3. Chronic poisonings: by faster metabolism of till the inducing agent is being given. Thereafter the accumulated poisonous substance. the enzymes return to their original value over 4. Liver disease. 1–3 weeks. First-pass (Presystemic) Metabolism Consequences of microsomal This refers to metabolism of a drug during its enzyme induction passage from the site of absorption into the sys­ 1. Decreased intensity and/or duration of action temic circulation. All orally administered drugs of drugs that are inactivated by metabo­ lism, are exposed to drug metabolizing enzymes in e.g. failure of contraception with oral contra­ the intestinal wall and liver (where they first ceptives and loss of anti-HIV action of nevirapine reach through the portal vein). Presystemic SECTION 1 due to rifampin coadministration. metabo­lism in the gut and liver can be avoided 2. Increased intensity of action of drugs that by adminis­tering the drug through sublingual, are activated by metabolism. Acute paracetamol transdermal or parenteral routes. However, lim- toxi­city is due to one of its metabolites—toxic- ited presystemic metabolism can occur in the ity occurs at lower doses in patients receiving skin (transdermally administered drug) and in enzyme inducers. lungs (for drug reaching venous blood through 3. Tolerance—if the drug induces its own any route). The extent of first pass metabolism metabo­­lism (autoinduction), e.g. carbamazepine, differs for different drugs (Table 3.2) and is an rifampin; nevirapine dose needs to be doubled important determinant of oral bio­ availability. after 2 weeks. A drug can also be excreted as such into 4. Some endogenous substrates (steroids, bili­ bile. The hepatic extraction ratio (ERLiver) of rubin) are also metabolized faster. a drug is the fraction of the absorbed drug 5. Precipitation of acute intermittent porphyria: prevented by the liver from reaching systemic enzyme induction increases porphyrin synthesis circulation. Both presystemic metabolism as well by derepressing δ-aminolevulinic acid synthe­tase. as direct excretion into bile determine ERLiver, 6. Intermittent use of an inducer may interfere which is given by the equation: with adjustment of dose of another drug pres­ CLLiver cribed on regular basis, e.g. oral anticoagulants, ER = ..(1) oral hypoglycaemics, antiepileptics, antihyper­ Hepatic blood flow ten­sives. Accordingly the systemic bioavailability (F) 7. Interference with chronic toxicity testing of an orally administered drug will be: in animals. F = fractional absorption × (I–ER)..(2) Drugs whose metabolism is significantly When a drug with high first pass metabolism is given orally affected by enzyme induction are—phenytoin, at higher dose to achieve therapeutic blood levels, the plasma carbamazepine, antidepressants, warfarin, tol- concentration of its metabolites will be much higher compared to those resulting from parenteral dosing of the drug for the butamide, oral contra­ceptives, chloramphenicol, same therapeutic level. If the metabolites contribute to the doxycycline, theo­phylline, gri­seo­fulvin, nevirap- adverse effects of the drug, oral dosing will be less safe than ine. parenteral.  Metabolism and Excretion of Drugs, kinetics of elimination 35 Table 3.2: Extent of hepatic first pass metabolism of some important drugs Low Intermediate High not given orally high oral dose Phenobarbitone Aspirin Isoprenaline Propranolol Phenylbutazone Quinidine Lidocaine Alprenolol Tolbutamide Desipramine Hydrocortisone Verapamil Theophylline Nortriptyline Testosterone Salbutamol Pindolol Chlorpromazine Glyceryl trinitrate Diazepam Pentazocine Morphine Isosorbide Metoprolol Pethidine mononitrate Attributes of drugs with high first pass by enteric bacteria is reabsorbed (entero­hepatic metabolism: cycling) and ultimate excretion occurs in urine (a) Oral dose is considerably higher than sub­ (Fig. 3.2). Only the remaining is excreted in lingual or parenteral dose. the faeces. Enterohepatic cycling contributes (b) There is marked individual variation in the to longer stay of the drug in the body. Drugs CHAPTER 3 oral dose due to differences in the extent of that attain high concentrations in bile include first pass metabolism. erythro­mycin, ampicillin, rifampin, tetra­cyc­line, (c) Oral bioavailability is apparently increased oral contraceptives, vecuronium, phenolphthalein. in patients with severe liver disease. Certain drugs are excreted directly in colon, (d) Oral bioavailability of a drug is increased e.g. anthracene purgatives, heavy metals. if another drug competing with it in first pass 3. Exhaled air Gases and volatile liquids metabolism is given concurrently, e.g. chlorpro­ (general anaesthetics, alcohol) are eliminated mazine and propranolol. by lungs, irrespective of their lipid solubility. Alveolar transfer of the gas/vapour depends EXCRETION on its partial pressure in the blood. Lungs Excretion is the passage out of systemically also serve to trap and extrude any parti­culate absorbed drug. Drugs and their metabolites matter that enters circulation. are excreted in: 4. Saliva and sweat These are of minor 1. Urine Drug excretion in urine occurs via impor­tance for drug excretion. Lithium, pot. the kidney. It is the most important channel of iodide, rifampin and heavy metals are pres- excretion for majority of drugs (see below). ent in these secretions in significant amounts. Most of the saliva along with the drug in it, 2. Faeces Apart from the unabsorbed frac­ is swallowed and meets the same fate as orally tion, most of the drug present in faeces is taken drug. derived from bile. Liver actively transports into bile orga­nic acids (especially drug gluc- 5. Milk The excretion of drug in milk is uronides by OATP and MRP2), organic bases not important for the mother, but the suckling (by OCT), other lipophilic drugs (by P-gp) and infant inadvertently receives the drug. Most steroids by distinct non­specific active transport drugs enter breast milk by passive diffusion. As mechanisms. Relatively larger mole­cules (MW such, more lipid soluble and less protein bound > 300) are prefe­ren­­tially eliminated in the bile. drugs cross better. Milk has a lower pH (7.0) Most of the free drug in the gut, inclu­ ding than plasma, basic drugs are somewhat more that relea­sed by deconju­gation of glucu­ro­nides concentrated in it. However, the total amount of  36 GENERAL PHARMACOLOGY SECTION 1 Fig. 3.2: Enterohepatic cycling of drugs In the liver many drgus (D), including steroids, are conjugated by the enzyme UDP-glucuronosyl transferases (UGTs) to form drug-glucuronide (DG). Part of the DG enters systemic circulation and is excreted into urine by the kidney through both glomerular filtration (GF) as well as active tubular secretion involving renal organic-anion transporting peptide (OATP). Another part of DG is actively secreted into bile by the hepatic OATP. On reaching the gut lumen via bile, a major part of DG is deconjugated by becterial hydrolytic enzymes (deconjugases) while the remaining is excreted into faeces. The released D is reabsorbed from the gut to again reach the liver through portal circulation and complete the enterohepatic cycle. drug reaching the infant through breast feeding (Glomerular filtration + is generally small and majority of drugs can Net renal = tubular secretion) – tubular be given to lactating mothers without ill effects excretion reabsorption on the infant. Never­theless, it is advisable to administer any drug to a lactating woman only Glomerular filtration Glomerular capillaries when essential. Drugs that are safe, as well as have pores larger than usual; all nonprotein those contraindicated during breast feeding or bound drug (whether lipid-soluble or insoluble) need special caution are given in Appendix-3 presented to the glomerulus is filtered. Thus, at the end of the book. glomerular filtration of a drug depends on its plasma protein binding and renal blood flow. RENAL EXCRETION Glomerular filtration rate (g.f.r.), normally ~ 120 ml/min, declines pro­gressively after the The kidney is responsible for excreting all age of 50, and is low in renal failure. Glo- water soluble substances. The amount of drug merular filtration of drugs declines in parallel. or its meta­bolites ultimately present in urine is the sum­­ total of glomerular filtration, tubular Tubular reabsorption This occurs by passive reabsorp­tion and tubular secretion (Fig. 3.3). diffusion and depends on the lipid solubility  Metabolism and Excretion of Drugs, kinetics of elimination 37 outcome. The effect of changes in urinary pH on drug excretion is greatest for those having pKa values between 5 to 8, because only in their case pH dependent passive reabsorption is signi­ficant. Tubular secretion This is the active transfer of organic acids and bases by two separate classes of relatively nonspecific transporters (OAT and OCT) which operate in the prox­ imal tubules. In addition, efflux transporters P-gp and MRP2 are located in the luminal membrane of proximal tubular cells. If renal clearance of a drug is greater than 120 mL/ min (g.f.r.), additional tubular secretion can be assumed to be occurring. Active transport of the drug across tubules reduces concentration of its free form in the tubu­ l ar vessels and promotes dissociation CHAPTER 3 Fig. 3.3: Schematic depiction of glomerular filtration, tubular reabsorption and tubular secretion of drugs of protein bound drug, which then becomes FD—free drug; BD—bound drug; UD—unionized drug; available for secretion (Fig. 3.3). Thus, pro­tein ID—ionized drug; Dx—actively secreted organic acid (or binding, which is a hindrance for glomeru­ lar base) drug filtration of the drug, is not so (may even be facilitatory) to excretion by tubular secretion. and ionization of the drug at the existing (a) Organic acid transport (through OATP) urinary pH. Lipid-soluble drugs filtered at the operates for penicillin, probe­ ne­­ cid, uric acid, glomerulus back diffuse in the tubules because salicylates, indomethacin, sulfinpyrazone, nitro­ 99% of glomerular filtrate is reabsorbed, but furantoin, methotrexate, drug glucuronides and nonlipid-soluble and highly ionized drugs are sulfates, etc. unable to do so. Thus, rate of excretion of (b) Organic base transport (through OCT) such drugs, e.g. aminogly­ coside antibiotics, operates for thiazides, amiloride, triamterene, qua­ternary ammo­nium compounds parallels g.f.r. furosemide, quinine, procainamide, choline, (or creatinine clearance). Changes in urinary cimetidine, etc. pH affect tubular reabsorption of drugs that Inherently both transport processes are bi­ are partially ionized— directional, i.e. they can transport their sub­ Weak bases ionize more and are less reabsor­ strates from blood to tubular fluid and vice bed in acidic urine. versa. How­ever, for drugs and their metabolites Weak acids ionize more and are less reabsor­ (exogenous substances) secretion into the tu- bed in alkaline urine. bular lumen predominates, whereas an endog- This principle is utilized for facilitating elimina­tion enous substrate like uric acid is predominantly of the drug in poisoning, i.e. urine is alkali­nized reabsorbed. in barbiturate and salicylate poisoning. Though Drugs utilizing the same active transport elimination of weak bases (morphine, amphetamine) com­pete with each other. Probenecid is an orga­ can be enhanced by acidifying urine, this is not nic acid which has high affinity for the tubular practiced clinically, because acidosis can induce OATP. It blocks the active trans­ port of both rhabdomyolysis, cardiotoxi­city and actually worsen penicillin and uric acid, but whereas the net  38 GENERAL PHARMACOLOGY excretion of the former is decreased, that of the latter is increased. This is because penicillin is primarily secreted while uric acid is primarily reabsorbed. Many drug interactions occur due to competition for tubular secretion, e.g. (i) Aspirin blocks uricosuric action of probene­ cid and sulfinpyrazone and decrease tubular secretion of methotrexate. (ii) Probenecid decreases the concentration of nitrofurantoin in urine, increases the duration of action of penicillin/ampicillin and impairs secretion of methotrexate. Fig. 3.4: Illustration of the concept of drug clearance. (iii) Sulfinpyrazone inhibits excretion of tolbuta­ A fraction of the drug molecules present in plasma are mide. removed on each passage through the organs of elimina- tion. In the case shown, it requires 50 mL of plasma to (iv) Quinidine decreases renal and biliary clea­ account for the amount of drug being eliminated every rance of digoxin by inhibiting efflux carrier P-gp. minute: clearance is 50 mL/min Tubular transport mechanisms are not well developed at birth. As a result, duration of action Clearance (CL) The clearance of a drug is SECTION 1 of many drugs, e.g. penicillin, cephalosporins, the theoretical volume of plasma from which aspirin is longer in neonates. These systems the drug is completely removed in unit time mature during infancy. Renal function again (analogy creati­nine clearance; Fig. 3.4). It can progressively declines after the age of 50 years; be calculated as: renal clearance of most drugs is substantially   CL = Rate of elimination/C...(3) lower in the elderly (>75 yr). where C is the plasma concentration. For majority of drugs the processes involved KINETICS OF ELIMINATION in elimination are not saturated over the clini­ The knowledge of kinetics of elimination of a cally obtained concentrations, they follow: drug provides the basis for, as well as serves to First order kinetics The rate of elimination is devise rational dosage regimens and to modify directly proportional to the drug con­cen­tration, them according to individual needs. There are CL remains constant; or a constant fraction of three fundamental pharmacokinetic parameters, the drug present in the body is eliminated in viz. bioavailability (F), volume of distribution (V) unit time. This applies to majority of drugs and clearance (CL) which must be understood. which do not saturate the elimination processes The first two have already been considered. (trans­porters, enzymes, blood flow, etc.) over Drug elimination is the sumtotal of metabolic the therapeutic concentration range. However, if inactivation and excretion. As depicted in Fig. the dose is high enough, elimination pathways 2.1, drug is eliminated only from the central of all drugs will get saturated. compartment (blood) which is in equilibrium Few drugs normally saturate eliminating with peripheral compartments including the site mec­ha­nisms and are handled by— of action. Depending upon the ability of the body to eliminate a drug, a certain fraction Zero order kinetics The rate of elimi­nation of the central compartment may be considered remains constant irrespective of drug concen­ to be totally ‘cleared’ of that drug in a given tration, CL decreases with increase in concen­ period of time to account for elimination over tration; or a constant amount of the drug is that period. eliminated in unit time, e.g. ethyl alcohol. This  Metabolism and Excretion of Drugs, kinetics of elimination 39 is also called capacity limited elimination or Michaelis-Menten elimination. The elimination of some drugs approaches saturation over the therapeutic range, kinetics changes from first order to zero order at higher doses. As a result plasma concentration increases disproportionately with increase in dose (see Fig. 3.6), as occurs in case of phenytoin, tol- butamide, theophylline, warfarin. Since the dose rate-plasma concentration plot in this case is curved, it is also called ‘nonlinear elimination’. Blood flow dependent elimination For few drugs the eliminating capacity of an organ of elimination (kidney, liver) far exceeds the amount of drug normally presented to it by blood circulation. The elimination of such a drug becomes blood flow dependent. These Fig. 3.5: Semilog plasma concentration-time plot of a drug eliminated by first order kinetics after intravenous injection highly extracted drugs are almost completely CHAPTER 3 eliminated in a single passage through the organ of elimination. Plasma half-life The Plasma half-life (t½) Since first order kinetics is an exponential of a drug is the time taken for its plasma process, mathematically, the elimination t½ is concen­tration to be reduced to half of its original value. ln2 t½ = ——...(4) Taking the simplest case of a drug which k has rapid one compartment distribution and first Where ln2 is the natural logarithm of 2 (or order elimination, and is given i.v. a semilog 0.693) and k is the elimination rate constant of plasma concentration-time plot as shown in the drug, i.e. the fraction of the total amount Fig. 3.5 is obtained. The plot has two slopes. of drug in the body which is removed per initial rapidly declining (α) phase—due to unit time. For example, if 2 g of the drug is distribution. present in the body and 0.1 g is eliminated later less declined (β) phase—due to elimina­ every hour, then tion. At least two half-lives (distribution t½ and k = 0.1/2 = 0.05 or 5% per hour. elimination t½) can be calculated from the It is calculated as: two slopes. The elimination half life derived CL from the β slope is simply called the ‘half     k = —­–...(5) life’ of the drug.   V Most drugs infact have multicompartment distribution and    V multiexponential decay of plasma concentration-time plot. therefore t½ = 0.693 × ——...(6) Half-lives calculated from the terminal slopes (when plasma  CL concentrations are very low) are excep­tionally long, probably As such, half-life is a derived parameter from due to release of the drug from slow equilibrating tissues, two variables V and CL, both of which may enterohepatic circulation, etc. Only the t½ calculated over the steady-state plasma concentration range is clinically relevant. change independently. It, therefore, is not an It is this t½ which is commonly mentioned. exact index of drug elimination. Nevertheless,  40 GENERAL PHARMACOLOGY it is a simple and useful guide to the sojourn The dose rate-Cpss relationship is linear only of the drug in the body, i.e. after in case of drugs eliminated by first order 1 t½–50% drug is eliminated. kinetics. For drugs (e.g. phenytoin) which 2 t½–75% (50 + 25) drug is eliminated. follow Michaelis Menten kinetics, elimina-  3 t½–87.5% (50 + 25 + 12.5) drug is tion changes from first order to zero order    eliminated. kinetics over the therapeutic range. Increase 4 t½–93.75% (50 + 25 + 12.5 + 6.25) drug in their dose beyond saturation levels causes is eliminated. an increase in Cpss which is out of propor- Thus, nearly complete drug elimination occurs tion to the change in dose rate (Fig. 3.6). in 4–5 half lives. In their case: For drugs eliminated by— First order kinetics—t½ remains constant because    (Vmax) (C) V and CL do not change with dose. Rate of drug elimination = ————...(10) Zero order kinetics—t½ gets prolonged with    Km + C dose because CL progressively decreases as where C is the plasma concentration of the drug, dose is increased. In fact, the concept of t½ Vmax is the maximum rate of drug elimination, is meaningless for such drugs, because, it is and Km is the plasma concentration at which not a fixed value. elimination rate is half maximal. SECTION 1 Half life of some representative drugs Plateau principle Aspirin 4 hr Digoxin 40 hr When constant dose of a drug is repeated before Penicillin-G 30 Digitoxin 7 days the expiry of 4 t½, it would achieve higher min peak concentration, because some remnant of the Doxycycline 20 hr Phenobarbitone 90 hr previous dose will be present in the body. This continues with every dose until progressively Repeated drug administration increasing rate of elimination (which increases When a drug is repeated at relatively short with increase in concentration) balances the inter­v als, it accumulates in the body until amount administered over the dose interval. elimination balances input and a steady state Subsequently plasma concentration plateaus plasma concen­tration (Cpss) is attained— dose rate Cpss = —————...(7)    CL From this equation it is implied that doubling the dose rate would double the average Cpss and so on. Further, if the therapeutic plasma concen­tration of the drug has been worked out and its CL is known, the dose rate needed to achieve the target Cpss can be determined— dose rate = target Cpss × CL...(8) After oral administration, often only a fraction (F) of the dose reaches systemic circulation in the active form. In such a case— target Cpss × CL Fig. 3.6: Relationship between dose rate and average dose rate = ————————...(9) steady-state plasma concentration of drugs eliminated F by first order and Michaelis Menten (zero order) kinetics  Metabolism and Excretion of Drugs, kinetics of elimination 41 and fluctuates about an average steady-state plasma concentration which has been defined level. This is known as the plateau principle to be in the therapeutic range; such data are of drug accu­ mulation. Steady-state is reached now available for most drugs of this type. in 4–5 half lives unless dose interval is very Drugs with short t½ (upto 2–3 hr) adminis­tered much longer than t½ (Fig. 3.7). at conventional intervals (6–12 hr) achieve the target levels only intermittently and fluctua­tions in plasma concentration are marked. In case of many drugs (penicillin, ampicillin, chloramp­he­­ nicol, erythromycin, propranolol) this how­ever is therapeutically acceptable. For drugs with longer t½ a dose that is sufficient to attain the target concentration after single admi­n is­tration, if repeated will accumu­late according to plateau principle and produce toxicity later on. On the other hand, if the dosing is such as to attain target level at steady state, the therapeutic effect will be delayed by about 4 half lives (this may be CHAPTER 3 clinically unacceptable). Such drugs are often administered by initial loading and subsequent Fig. 3.7: Plateau principle of drug accumulation on maintenance doses. repeated oral dosing. Note. The area of the two shaded portions is equal Loading dose This is a single or few quickly repeated doses given in the beginning The amplitude of fluctuations in plasma to attain target concentration rapidly. It may concentration at steady-state depends on the dose be calculated as— interval relative to the t½, i.e. the difference between the maximum and minimum levels  target Cp × V is less if smaller doses are repeated more Loading dose = ——————    ...(11) frequently (dose rate remaining constant). Dose F intervals are gene­ rally a compromise between Thus, loading dose is governed only by V and what ampli­tude of fluctuations is clinically not by CL or t½. acceptable (because of loss of efficacy at troughs Maintenance dose This dose is one that is and side effects at peaks) and what frequency to be repeated at specified intervals after the of dosing is convenient. However, if the dose attainment of target Cpss so as to maintain rate is changed, a new average Cpss is attained the same by balancing elimination. The main- over the next 4–5 half lives. When the drug tenance dose rate is computed by equation (9) is administered orally (absorption takes some and is governed by CL (or t½) of the drug. If time), average Cpss is approximately 1/3 of facilities for measurement of drug concentration the way between the minimal and maximal are available, attainment of target level in a levels in a dose interval. patient can be verified subsequently and dose Target level strategy For drugs whose effects rate adjusted if required. are not easily quantifiable and safety margin Such two phase dosing provides rapid thera­ is not big, e.g. anticonvulsants, antidepressants, peutic effect with long term safety; frequently lithium, antiarrhythmics, theophylline, some anti­ applied to digoxin, chloroquine, long-acting microbials, etc. or those given to prevent an sulfona­mides, doxycycline, amiodarone, etc. event, it is best to aim at achieving a certain However, if there is no urgency, maintenance  42 GENERAL PHARMACOLOGY doses can be given from the beginning. The and depends on the purpose of TDM as well as the concept of loading and maintenance dose is valid nature of the drug. a. When the purpose is dose adjustment: In case of drugs also for short t½ drugs and i.v. administration which need to act continuously (relatively long-acting in critically ill patients, e.g. lidocaine (t½ 1.5 drugs), it is prudent to measure the trough steady-state hr) used for cardiac arrhythmias is given as an blood levels, i.e. just prior to the next dose, because i.v. bolus dose followed by slow i.v. infusion this is governed by both V and CL. On the other hand, for short-acting drugs which achieve therapeutic levels or intermittent fractional dosing. only intermittently (e.g. ampicillin, gentamicin), sampling is done in the immediate post-absorptive phase (usually Monitoring of plasma concentration of after 1–2 hours of oral/i.m. dosing) to reflect the peak drugs It is clear from the above consider- levels. ations that the Cpss of a drug attained in a b. In case of poisoning: Blood for drug level estimation given patient depends on its F, V and CL in should be taken at the earliest to confirm the poison- ing and to assess its seriousness. It should then be that patient. Because each of these parameters repeated at intervals to estimate the drug clearance in varies considerably among individuals, the the affected patient, and the need to hasten elimination actual Cpss in a patient may be 1/3 to 3 times (e.g. by haemodialysis). that calculated on the basis of population data. c. For checking compliance to medication: Even random blood sampling can be informative. Measurement of plasma drug concentration can give an estimate of the pharmacokinetic Monitoring of plasma concentration is of variables in that patient and the magnitude of SECTION 1 no value for deviation from the ‘average patient’, so that 1. Drugs whose response is easily measurable, appropriate adjust­ments in the dosage regimen e.g.— antihypertensives, hypoglycaemics, can be made. diu­re­­tics, oral anticoagulants, inhalational In case of drugs obeying first order kinetics: general anaes­thetics. 2. Drugs activated in the body, e.g.—levodopa. Previous dose rate × Target Cpss 3. ‘Hit and run drugs’ (whose effect lasts much Revised = ——————————————...(12) dose rate Measured Cpss longer than the drug itself), e.g.—reserpine, guane­­thi­dine, MAO inhibitors, omeprazole. Therapeutic drug monitoring (TDM) is parti­ 4. Drugs with irreversible action, e.g.—organo­ cularly useful in the following situations: phos­phate anticholinesterases, phenoxybenza­ 1. Drugs with low safety margin, e.g. —digoxin, mine. anti­convulsants, antiarrhythmics, theophylline, aminoglycoside antibiotics, lithium, tricyclic PROLONGATION OF DRUG ACTION antidepressants. 2. If individual variations are large, e.g.—anti­ It is sometimes advantageous to modify a drug depres­sants, lithium. in such a way that it acts for a longer period. 3. Potentially toxic drugs used in the presence By doing so: of renal failure, e.g. —aminoglycoside anti- (i) Frequency of administration is reduced— biotics, vancomycin. more convenient. 4. In case of poisoning. (ii) Improved patient compliance—a single morn- 5. In case of failure of response without any ing dose is less likely to be forgotten/omitted apparent reason, e.g. —antimicrobials. than a 6 or 8 hourly regimen; a monthly or 6. To check patient compliance, e.g. —psycho­ quarterly administered contraceptive over one phar­macological agents. that has to be taken daily. Selection of the correct interval between drug administra­ (iii) Large fluctuations in plasma concentration tion and drawing of blood sample for TDM is critical, are avoided—side effects related to high peak  Metabolism and Excretion of Drugs, kinetics of elimination 43 plasma level just after a dose (e.g. nifedipine) the drug may be more variable than the regular would be mini­ mized; better round-the-clock tablet of the same drug. control of blood sugar level, etc. (iv) Drug effect could be maintained overnight (b) Parenteral The s.c. and i.m. injection of without disturbing sleep, e.g. antiasthmatics, drug in insoluble form (benzathine penicillin, lente anticonvulsants, etc. insulin) or as oily solution (depot progestins); However, all drugs do not need to be made pellet implantation, sialistic and biodegradable long acting, e.g. those used for brief therapeutic implants can provide for its absorption over effect (sleep-inducing hypnotic, headache remedy) a couple of days to several months or even or those with inherently long duration of action years. Inclusion of a vasoconstrictor with the (doxycycline, omeprazole, digoxin, amlodipine). drug also delays absorption (adrenaline with Drugs with t½ < 4 hr are suitable for con- local anaes­thetics). trolled release formu­lations, while there is no (c) Transdermal drug delivery systems The need of such formula­ tions for drugs with t½ drug impregnated in adhesive patches, strips or as >12 hr. Methods utilized for prolonging drug ointment applied on skin is utilized in some cases action are summarised below. Some of these to prolong drug action, e.g. GTN (see p. 12). have already been described. 2. By increasing plasma protein binding 1. By prolonging absorption from site of CHAPTER 3 administration Drug con­ge­ners have been prepared which are highly bound to plasma protein and are slowly (a) Oral Sustained release tablets, spansule released in the free active form, e.g. sulfadoxine. capsules, etc.; drug particles are coated with resins, plastic materials or other substances 3. By retarding rate of metabolism Small which temporally disperse release of the active chemical modification can markedly affect ingredient in the g.i.t. Another technique (con- the rate of metabolism without affecting the trolled release tablet/capsule; Fig. 3.8) utilizes a biologi­cal action, e.g. addition of ethinyl group semiper­meable membrane to control the release to estradiol (ethinyl estradiol) makes it longer of drug from the dosage form. Such prepara- acting and suitable for use as oral contracep- tions prolong the action by 4 to 8 hours and tive. Inhibition of specific enzyme by one no more, because in that time drug particles drug can prolong the action of another drug, reach the colon. Also, the drug release pattern e.g. allopurinol inhibits the degradation of and consequently the attained blood levels of 6-mercaptopurine, ritonavir boosts the levels of atazanavir/lopinavir/saquinavir, cilastatin protects imipenem from degradation in kidney. 4. By retarding renal excretion The tubu- lar secretion of drug being an active process, can be suppressed by a competing substance, e.g. probenecid prolongs duration of action of penicillin, ampicillin and amoxicillin. Targeted drug delivery devices Some new devices have been invented (and Fig. 3.8: Pattern of drug release from oral controlled many are under development) to localise and release tablet/capsule; 30% of the dose outside the prolong the delivery of the contained drug to semipermeable membrane is released immediately, while 70% of the dose is released slowly through the membrane a specific target organ. The ones already in over the next 4–8 hours use are:  44 GENERAL PHARMACOLOGY 1. Liposomes These are unilamellar or bila- 2. Drug releasing implants The implant is mellar nano-vesicles (60–80 nM) produced by coated with the drug using special techniques sonication of lecithin or other biodegradable and then placed in the target organ to provide phospholipids. Since liposomes injected i.v. are prolonged delivery of minute quantities of the selectively taken up by reticuloendothelial cells, drug by slow release. Progestin impregnated especially liver and spleen, and some malig- intrauterine contraceptive device (IUCD) affords nant cells, the drug incorporated in them gets protection for upto 5 years. It is also being selectively delivered to these cells. Liposomal tried for other gynaecological problems. Anti- amphotericin B is being used in Kala azar thrombotic drug coated stents (devices placed and some serious cases of systemic mycosis. in the thrombosed coronary artery after balloon Antibody tagging of liposomes is being tried angioplasty to keep it patent) are in use to as a means to target other specific tissues. prevent restenosis and failure of angioplasty.  Problem Directed Study 3.1 A 30-year-old mother of 2 children weighing 60 kg was taking combined oral contra- ceptive pill containing levonorgestrel 0.15 mg + ethinylestradiol 30 µg per day cyclically (3 SECTION 1 weeks treatment—1 week gap). She developed fever with cough and was diagnosed as a case of pulmonary tuberculosis after sputum smear examination. She was put on isoniazid (300 mg) + rifampin (600 mg) + pyrazinamide (1.5 g) + ethambutol (1.0 g) daily for 2 months, followed by isoniazid (600 mg) + rifampin (600 mg) thrice weekly. In the 3rd month she failed to have the usual withdrawal bleeding during the gap period of contraceptive cycle. After 10 days her urinary pregnancy test was found to be positive. (a) What could be the reason for failure of the oral contraceptive? (b) What precaution could have prevented the unwanted pregnancy? 3.2 A 20-year-old patient weighing 60 kg has to be prescribed an antiepileptic drug (avail- able as 200 and 400 mg tablets) for generalized tonic-clonic seizures. The pharmacokinetic parameters and therapeutic plasma concentration of the selected drug are: Target steady-state plasma concentration (Cpss) – 6 mg/L Oral bioavailability (F) – 70% Volume of distribution (V) – 1.4 L/kg Clearance (CL) – 80 ml/hr/kg Plasma half life (t½) – 15 hours What should be the loading dose and the daily maintenance dose of the drug for this patient? (see Appendix-1 for solutions)