Pharmacokinetics: Absorption PDF

PHARMACOKINETICS: Absorption Pharmacokinetics Pharmacokinetics refers to the movement of drugs into, through and out of the body. The nature of the response of an individual to a particular drug depends on the inherent pharmacological properties of the drug at its site of action, but t...

PHARMACOKINETICS: Absorption Pharmacokinetics Pharmacokinetics refers to the movement of drugs into, through and out of the body. The nature of the response of an individual to a particular drug depends on the inherent pharmacological properties of the drug at its site of action, but the speed of onset, the intensity and the duration of the response usually depend on parameters such as:  the rate and extent of uptake of the drug from its site of administration;  the rate and extent of distribution of the drug to different tissues, including the site of action;  the rate of elimination of the drug from the body.  ADME The core of pharmacokinetics is based on four processes, sometimes referred to collectively as ADME: Absorption—The transfer of the drug from its site of administration to the general circulation. Distribution—The transfer of the drug from the general circulation into the different tissues of the body. Metabolism—The extent to which the drug molecule is chemically modified in the body. Excretion—The removal of the parent drug and any metabolites from the body; metabolism and excretion together account for drug elimination. THE BIOLOGICAL BASIS OF PHARMACOKINETICS  Passage Across Membranes With the exception of intravenous or intraarterial injections, a drug must cross at least one membrane in its movement from the site of administration into the general circulation. Drugs acting at intracellular sites must also cross the cell membrane to exert an effect. The main mechanisms by which drugs can cross membranes are:  passive diffusion through the lipid layer,  diffusion through pores or ion channels,  carrier-mediated processes,  pinocytosis. Fig. The passage of drugs across membranes. Molecules can cross the membrane by simple passive diffusion through the lipid bilayer or via a channel, or by facilitated diffusion, or by ATP-dependent active transport. ABC, ATP- binding cassette superfamily of transport proteins; D, drug; NBD, nucleotide-binding domain; SLC, solute carrier super- family of transporters; TMD, transmembrane domain  Passive diffusion To dissolve in body fluids a drug usually needs a degree of aqueous solubility, but to cross a phospholipid bilayer by direct diffusion, it must have a degree of lipid solubility, such as that shown by ethanol or steroids. All drugs can move passively down a concentration gradient, and when a concentration gradient occurs across a membrane permeable to the drug, then a state of equilibrium will eventually be reached in which equal concentrations of the diffusible form of the drug are present in solution on each side of the membrane. The net rate of diffusion is directly proportional to the concentration gradient across the membrane, and to the area and permeability of the membrane, but inversely proportional to its thickness (Fick’s law). Passage through membrane pores or ion channels Movement through channels occurs down a concentration gradient and is restricted to extremely small water- soluble molecules (>diffusion into the hepatic portal circulation, >>metabolism within the cell or transportation back into the gut lumen (by P-gp) The substrate specificities of CYP3A4 and P-gp overlap, and for common substrates, their combined actions can prevent most of the oral dose of some drugs reaching the hepatic portal circulation. 3-Liver Blood from the intestine is delivered by the hepatic portal circulation directly to the liver, which is the major site of drug metabolism in the body. Hepatic first-pass metabolism can be avoided by administering the drug to a region of the gut from which the blood does not drain into the hepatic portal vein (e.g. the buccal cavity or rectum); a good example of this is the buccal administration of glyceryl trinitrate.  Drugs that avoid or survive hepatic first-pass metabolism after administration and enter the systemic circulation may nevertheless undergo repeated cycles of hepatic metabolism on subsequent passes through the liver from the hepatic artery. 4-Lung Cells of the lungs have high affinities for many basic drugs and are the main site of metabolism for many local hormones via monoamine oxidase or peptidase activity.  Absorption From Other Routes Percutaneous (Transcutaneous) Administration The human epidermis (especially the stratum corneum) is an effective permeability barrier to water loss and to the transfer of water-soluble compounds. Although lipid-soluble drugs can cross this barrier, the rate and extent of entry are very limited. Consequently, this route is only effective for use with potent, non- irritant drugs such as glyceryl trinitrate or fentanyl, or to produce a local effect. The slow and continued absorption from dermal administration (e.g. via adhesive patches) can be used to produce low but relatively constant blood concentrations of some drugs (e.g. nicotine replacement therapy). Absorption From Other Routes Intradermal and Subcutaneous Injection Intradermal or subcutaneous injection avoids the barrier presented by the stratum corneum, and entry into the general circulation is limited mainly by the rate of blood flow to the site of injection. However, these sites generally only allow the administration of small volumes of drugs and tend to be used mostly for local effects, such as local anesthesia, or to deliberately limit the rate of drug absorption, such as insulin glargine that precipitates on subcutaneous injection, creating a depot that liberates insulin slowly. Subdermal implants are increasingly used for long-term hormonal contraception. The implants are flexible polymer rods or tubes inserted under the skin of the upper arm that slowly release the hormone for up to 3 years, with contraception being reversible by removal of the implant. Absorption From Other Routes Intramuscular Injection The rate of absorption from an intramuscular injection depends on two variables: the local blood flow and the water solubility of the drug.  An increase in either of these factors enhances the rate of removal from the injection site. Absorption of drugs from the injection site can be prolonged intentionally by incorporation of the drug into a lipophilic vehicle, such as flupentixol decanoate, creating a depot formulation in a small volume of thin vegetable oil from which the drug is released over days or weeks. Absorption From Other Routes Intranasal Administration The nasal mucosa provides a good surface area for absorption and has low levels of proteases and drug- metabolising enzymes compared with the gastrointestinal tract. As a consequence, the intranasal route is used for the administration of some drugs, such as triptan drugs for migraines and desmopressin, as well as drugs designed to produce local effects, such as nasal decongestants and topical corticosteroids. Absorption From Other Routes Inhalation Although the lungs possess the characteristics of a good site for drug absorption (a large surface area and extensive blood flow), inhalation is rarely used to produce systemic effects. The principal reasons for this are the difficulty of delivering nonvolatile drugs to the alveoli and the potential for local toxicity to alveolar membranes. Drug administration by inhalation is therefore largely restricted to: volatile compounds, such as general anesthetics; locally-acting drugs, such as bronchodilators and corticosteroids used in the treatment of airway disease such as asthma and chronic obstructive pulmonary disease. Rate of Absorption The rate of absorption after oral administration is determined by the rate at which the drug is able to pass from the gut lumen into the systemic circulation. Following oral doses of some drugs, particularly lipid-soluble drugs with very rapid absorption, it may be possible to see three distinct phases in the plasma concentration–time curve, which reflect distinct phases of absorption, distribution and elimination  Rate of Absorption For most drugs, however, slow absorption masks the distribution phase A number of factors can influence this pattern:  Gastric emptying. Basic drugs undergo negligible absorption from the stomach, so there can be a delay of up to an hour between drug administration and the detection of drug in the general circulation.  Food. Food in the stomach slows drug absorption and also gastric emptying.  Rate of Absorption  Decomposition or first-pass metabolism before or during absorption. This will reduce the amount of drug that reaches the general circulation but will not affect the rate of absorption, which is usually determined by lipid solubility.  Modified-release formulations. If a drug is eliminated rapidly, the plasma concentrations will show rapid fluctuations during regular oral dosing, and to maintain a therapeutic plasma concentration it may be necessary to take the drug at very frequent intervals, which can reduce adherence to the intended regimen. The frequency with which a drug is taken can be reduced by giving a modified- release formulation that releases drug at a slower rate. The plasma concentration then becomes more dependent on the rate of absorption than the rate of elimination.  Extent of Absorption Bioavailability (F) is defined as the fraction of the administered dose that reaches the systemic circulation as the parent drug (unaltered, not as metabolites). For intravenous administration, the bioavailability (F) is therefore 1, as 100% of the parent drug enters the general circulation. For oral administration, bioavailability may also be complete (F = 1) or it may be incomplete (F < 1) resulting from:  incomplete absorption and loss in the feces because the tablet or capsule failed to disintegrate fully, or because the drug molecules did not fully dissolve, or are adsorbed onto gut contents, or are insufficiently lipid-soluble to be absorbed; or Extent of Absorption  first-pass metabolism in the gut lumen, during passage across the gut wall or by the liver before the absorbed drug reaches the systemic circulation. The bioavailability of a drug has important therapeutic implications because it is the major factor determining the equivalent drug dosage for different routes of administration. For example, if a drug has an oral bioavailability (F) of 0.1, the oral dose needed for therapeutic effectiveness will need to be 10 times higher than the corresponding intravenous dose (F = 1). Extent of Absorption The bioavailability is a characteristic of the drug and, providing that If the oral and intravenous (IV) doses absorption and elimination are not saturated, it is independent of administered are equal: the drug dose, meaning that the same proportion of a large dose will be absorbed into the circulation as with a small dose of the same drug. Bioavailability is normally determined by comparison of plasma concentrations measured after oral administration (when the fraction F of the parent drug enters the general circulation) with measurements following intravenous administration (when, by definition, F = 1). The amount in the circulation cannot be compared at a single time point, because intravenous and oral dosing show different concentration–time profiles, so instead the total area under the plasma concentration–time curve (AUC) from t = 0 to t = infinity is used, as this reflects the total amount of drug that has entered the general circulation. References