504 Pharm Drug Disposition Ii

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504 PHARM DRUG DISPOSITION II

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504 PHARM DRUG DISPOSITION II

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Consequences of drug metabolism

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1. Produces more polar, less lipid soluble metabolites--> better excreted.
2. pharmalogically inactivates the majority of drugs.
3. bioactivation of compounds: conversion of active drugs to INACTIVE PRODRUG to ACTIVE METABOLITE.

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What is the importance of drug metabolism?

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1. eliminating drugs
2. the cause of toxic responses to drugs.

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Where is the major site of drug metabolism? Others?

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Liver > intestine, plasma, kidneys, lungs >> brain

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What are the major types of metabolic reactions?

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1. Phase I metabolism
2. Phase II metabolism

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Phase I Metabolism

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Oxidation, reduction, and hydrolysis reactions--> introduces functional groups--> increases polarity of drug--> causes inactivation of drug.

Can also bioactivate.

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Phase II Metabolism

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Conjugation reactions

Covalent coupling to endogenous sugar, a.a., other compound--> inc polarity of metabolite--> inactivation.

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Cytochromes P450 (CYP) Phase I

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1. metabolize many different lipophilic drugs.
2. are versatile catalytical hemoproteins
3. in ER of liver and other tissues.
4. oxidase system

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Conjugation reactions (Phase II) requires what?

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High energy cosubstrate.

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Glucuronide conjugation is catalyzed by?

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Glucuronyltransferases

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What is the most common Phase II metabolic reaction?

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R-OH + UDP-Glucuronic acid --> R-O-Glucuronic acid + UDP.

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Conjugation with glutathione is catalyzed by?

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Glutathione-S-transferases

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To predict whether a factor affecting one drug will affect another, you need to know:

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1. which enzymes are affected
AND
2. which drugs they metabolize.

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Consequences of altered drug metabolism depend on?

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1. whether the drug is normally inactivated or activated by metabolism.
2. therapeutic index

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Decreased activity for a drug that is inactivated by metabolism, what are the consequences of altered drug metabolism?

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1. decreased activity will lead to decreased clearance, increased half life, inc plasma drug [ ], inc clinical effect or toxicity.