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DRUG METABOLISM - PHARM {ST1}. BY RANJEET RAMAN. Toxicity: generation of toxic/teratogenic metabolites of a benign parent drug. Activity: generation of active metabolites of a parent drug.
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DRUG METABOLISM - PHARM {ST1} BY RANJEET RAMAN
Toxicity: generation of toxic/teratogenic metabolites of a benign parent drug. • Activity: generation of active metabolites of a parent drug. • Interactions: unexpected increase or decrease in drug conc. in the present of an inhibitor or inducer of metabolism.
Most oral drugs must pass through portal system first. Some drugs are avidly metabolized by hepatocytes. These drugs have high extraction rates, and their clearance depends on liver blood flow. • First-pass metabolism: only a small fraction of highly-extracted drug reaches systemic blood. Drugs with low extraction have negligible first-pass effects.
First-pass metabolism can be circumvented by changing route of delivery or by changing the rate of metabolism, such as by adding an inhibitor of metabolism. • Role of the Liver • Liver turns parent drug into more polar (water-soluble) conjugates, allowing easier excretion.
This is carried out by P450’s. Some drugs cannot be made more polar by P450’s. Such fat-soluble drugs are conjugated and adducted with bile, and eliminated in stool. • Both Phase I and Phase II enzymes are microsomal (membrane associated), often located in the smooth ER membrane.
PHASE I reactions • Oxidation, reduction, and hydrolysis. • Carried out by CYP450 enzymes, which catalyze these various reactions in different directions. CYP450 use iron as the final election donor or acceptor. Usually oxidize drugs. • There are various classes, but CPY3A4 and CPY2D6 are the most important for drug metabolism. They can oxidize thousands of drugs.
CYP450 located on cytoplasmic side of smooth ER membrane. • PHASE II reactions • “Conjugation reactions,” which include glucuronidation, acetylation, methylation, sulfation. • Catalyzed by various enzymes including glucuronyl transferases and sulfotransferases. • Conjugative enzymes located on lumenal side of smooth ER membrane.
Non- microsomal and extra-hepatic drug metabolism Some enzymes are cytosolic or mitochondrial. These include monoamine oxidase and proteases, as well as alcohol and aldehyde dehydrogenases. • (ethanol à acetaldehyde via alcohol dehydrogenase) (acetaldehyde à acetic acid via aldehyde dehydrogenase. BLOCKED by (Antiabuse?)
P450’s are actually located in most tissues. In the intestines, CYP3A4 may lower bioavailability and cause high first-pass metabolism. • Glucuronyl transferases are present in the kidney. • Inhibition and Induction of Metabolism • Inhibition of P450’s by drugs or xenobiotics is competitive and reversible.
Major P450 inhibitors include cimetidine (anti-ulcer), erythromycin (macrolide antibiotic), and ketoconazole (anti-fungal). • Inhibition is used clinically in the case of antiabuse, which inhibits aldehyde dehydrogenase.
Induction of P450’s occurs by transactivation, leading to increased mRNA. This is often highly class specific among the P450’s, but is always mediated by drug binding to upstream DNA enhancer elements. • Major P450 inducers include phenobarbital and carbamazepine (anti- convulsants) and Rifampin (antibiotic). • Rifampin induces 3A4, causing increased clearance of many drugs, like contraceptives.
Age and Metabolism • Neonates do not have functional glucuronyl tranferases, so they are very susceptible to Phase II metabolized drugs such as sulfa drugs. • Elderly patients have reduced liver blood flow, with resulting reduced Phase I metabolism. • Phase II reactions are well-preserved with age and severe liver disease!
Liver disease affects drug clearance (Phase I reactions) in two ways: • fibrosis reduces blood flow, reducing first-pass effects and producing high concentrations of parent drug. • loss of hepatocytes reduces magnitude of Phase I reactions.
Drugs are in vast excess of targets, which means they have first-order kinetics. There is a constant % effect regardless of the concentration of cellular targets. For instance, if you give three tablets, that will kill 84% of cancer cells, whether there are 104 or 107 cells present. This all relies on large excess of drug compared to targets, but targets are not saturated. This means that doubling the dose won’t double the drug’s effect.
In first-order kinetics, a constant % of drug is metabolized. In zero-order kinetics, a constant amount of drug is metabolized. Although drugs are in vast excess of their receptors/enzymes, drugs do NOT SATURATE their enzymes, so they have first-order kinetics. • Think of cellular targets as enzymes, and drug as the substrate. If you vary enzyme concentration, you get a straight line. If you vary substrate, you get the rectangular hyperbola.
For a rectangular hyperbola, the Kx is the point where effect is half-maximum. For a semi-log plot, it is called the pKx. In pharmacology, it’s called the ED50. • Ideally, the Kd for the efficacy curve is much lower than the Kd for the toxicity curve.
Drugs as inhibitors • Non-competitive inhibitors decrease Vmax but not Km. They reduce efficacy, but not potency. ED50 remains constant, but Vmax shifts down. Cannot be overcome by raising drug concentration. • Competitive inhibitors increase Km but not Vmax. They reduce potency, but not efficacy. ED50 increases, so semi-log curve shifts to the right. You can achieve normal potency by adding more drug.
Uncompetitive inhibitors decrease both Vmax and Km. • Y-intercept of Line weaver-Burke plot is 1/Vmax. X-intercept is -1/Km. • Half-lives • Dt = D0e-kt • T1/2 = 0.693/k
