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Vol. 49, Issue 4, 403-449, December 1997

Role of Pharmacokinetics and Metabolism in Drug Discovery and Development

Jiunn H. Lina and Anthony Y. H. Lu

Department of Drug Metabolism, Merck Research Laboratories, West Point, Pennsylvania

I. Introduction
II. Role of Pharmacokinetics and Metabolism in Drug Design
    A. Metabolism and Drug Design
        1. Hard drugs.
        2. Soft drugs.
        3. Active metabolites.
    B. Pharmacokinetics and Drug Design
        1. Absorption.
        2. Prodrugs.
        3. Distribution.
        4. Plasma half-life.
        5. Stereoselectivity.
III. Role of Metabolism in Drug Toxicity
    A. Species Differences in Metabolism
        1. Oxidation and conjugation.
        2. Induction.
        3. Inhibition.
        4. Sexual dimorphism.
    B. Species- and Tissue-Specific Toxicity
        1. Species-specific toxicity.
        2. Site-specific toxicity.
    C. Stereoselectivity and Toxicity
        1. Stereoselective metabolism.
        2. Stereoselective toxicity.
IV. Role of Pharmacokinetics and Metabolism in Drug Development
    A. In Vitro Studies of Drug Metabolism
        1. Determination of metabolic pathways.
        2. Identification of drug-metabolizing enzymes.
        3. Drug-drug interaction.
        4. Prediction of in vivo metabolic clearance.
    B. In Vitro Studies of Drug Absorption
        1. Extrapolation of in vitro absorption data.
        2. Extrapolation of animal absorption data.
    C. In Vitro Studies of Protein Binding
        1. In vitro/in vivo protein binding.
        2. Plasma and tissue protein binding.
        3. Protein binding displacement interactions.
V. Interindividual Variability: A Critical Issue in Drug Development
    A. Pharmacokinetic Variability
        1. Variability in absorption.
        2. Variability in binding.
        3. Variability in excretion.
    B. Pharmacogenetics of Drug Metabolism
        1. Polymorphism in drug oxidation.
        2. N-Acetylation polymorphism.
        3. S-Methylation polymorphism.
        4. Atypical butyrylcholinesterase.
VI. Conclusions
References

a   Address for correspondence: Jiunn H. Lin, WP26A-2044, Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486.

0031-6997/97/4904-0403$03.00/0
PHARMACOLOGICAL REVIEWS
Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics


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