drug metabolism pharm st1 n.
Skip this Video
Loading SlideShow in 5 Seconds..
DRUG METABOLISM - PHARM {ST1} PowerPoint Presentation
Download Presentation


140 Vues Download Presentation
Télécharger la présentation


- - - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript


  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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?)

  9. 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.

  10. 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.

  11. 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.

  12. 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!

  13. 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.


  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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