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Drug Metabolism (Christina H)

Drug Metabolism (Christina H) - Week 6 Drug Metabolism 1...

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Week 6 Drug Metabolism 1. Drug metabolism is carried out by enzymes 2. Reason for withdrawal often due to hepatotoxicity a. Usually also due to CYP(genes that encode drug-metabolizing enzymes) 3. Reasons for termination of drug a. Toxicity, clinical efficacy b. Human PK- only account for 10% now (40 yrs ago, it accounted for 40% huge improvement!) i. Why? Increased understanding of drug PK/PD in the 1990s 4. Metabolism- processes by which body acts on a drug a. Often leads to termination of drug action b. Can also lead to bioactivation (ie. prodrugs) 5. Sites of biotransferation (ie. lots of metabolizing enzymes) a. Liver!! b. Nose 6. Why liver? Portal vein a. First line of defense against toxic compounds or foreign compounds 7. Lipophilic drugs a. Most likely reabsorbed by kidneys b. Instead, liver will transform it via making it a hydrophilic cmpd so that kidneys can excrete it 8. Ex. Phenytoin (lipophilic) a. CYP will hydroxylate cmpd (make it more water-soluble) b. With the OH grp, the UGT enzymes will couple glucuronic acid to it i. Attached a VERY polar, water-soluble moiety to drug ii. Now, it can be excreted by the kidneys 9. Phase 1- CypP450 a. Phase II: glucornic acid, sulfate added to molecules to facilitate its excretion 10. Phase I a. Add functional grps or can expose a grp (via hydrolytic or reductive enzymes) i. Hydrolysis, reduction, oxidation 11. P450 enzymes a. Major drug metabolizing enzymes b. Discovered as a protein in the liver with spectra properties c. Inducible! Levels of P450 fluctuate depending on the amt of drugs in body d. Biochem reaction i. Adds O (reduction reaction) via Cyp450 NADh reducing enzyme 12. Remarkable versatility a. Enzyme is able to act on many diff i. Binding product- very hydrophobic binding pocket allows for the pocket to accommodate a wide range of drugs ii. Sulfur grp + heme makes Cyp an enzyme rather than just bind to O2 13. P450 oxidation reactions- various ways to add O to compounds a. Epoxidations b. Dealkylation c. Hydroxylation 14. Nomenclature- based on: a. Family- >40% of sequence identity i. Ie. all cytochromes in CYP1 have greater than 40% seq identity b. Subfamily- 40-55% of sequence identity c.
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