chapter  7
128 Pages

In Vitro Approaches for Studying the Inhibition of Drug-Metabolizing Enzymes and Identifying the Drug-Metabolizing Enzymes Responsible for the Metabolism of Drugs (Reaction Phenotyping) with Emphasis on Cytochrome P450

Brian W. Ogilvie, Etsuko Usuki, Phyllis Yerino, and Andrew Parkinson XenoTech LLC, Lenexa, Kansas, U.S.A.

I. INTRODUCTION

From a drug interaction and pharmacogenetic perspective, drugs can be evaluated for their victim and perpetrator potential. Victims are those drugs whose clearance is predominantly determined by a single route of elimination, such as metabolism by a single cytochrome P450 (CYP) enzyme. Such drugs have a high victim potential because a diminution or loss of that elimination pathway, either due to a genetic deficiency in the relevant CYP enzyme or due to its inhibition by another concomitantly administered drug, will result in a large decrease in clearance and a correspondingly large increase in exposure to the victim drug (e.g., area under the plasma concentration-time curve or AUC). Perpetrators are those drugs (or other environmental factors) that inhibit or induce the enzyme that is otherwise responsible for clearing a victim drug. Genetic polymorphisms

that result in the partial or complete loss of enzyme activity (i.e., the intermediate and poor metabolizer genotypes) can also be viewed as perpetrators because they have the same effect as an enzyme inhibitor, i.e., they cause a decrease in the clearance of-and an increase in exposure to-victim drugs. Likewise, genetic polymorphisms that result in the overexpression of enzyme activity [i.e., the ultrarapid metabolizer (UM) genotype] can be viewed as perpetrators because they have the same effect as an enzyme inducer: they cause an increase in the clearance of-and a decrease in exposure to-victim drugs. Several drugs, whose elimination is largely determined by their metabolism by CYP2C9, CYP2C19, or CYP2D6, three genetically polymorphic enzymes, are victim drugs because their clearance is diminished in poor metabolizers (PMs), i.e., individuals who are genetically deficient in one of these enzymes. Drugs whose disposition is dependent on uptake or efflux by a transporter or on metabolism by a drug-metabolizing enzyme other than CYP can also be considered from the victim/perpetrator perspective. From a drug interaction perspective, victim drugs are also known as objects, whereas perpetrators are also known as précipitants.