CLINICAL IMPLICATIONS OF ANTIDEPRESSANT PHARMACOKINETIC AND PHARMACOGENETICS

OBJECTIVE: TO review available data on pharmacokinetic and pharmacogen etic influences on the response to antidepressant therapy, analyze the mechanisms for and clinical significance of pharmacokinetic and pharm acogenetic differences, and explain the implications of pharmacokineti cs and pharmacogenetics for patient care. DATA SOURCES: A MEDLlNE sear ch of English-language clinical studies, abstracts, and review article s on antidepressant pharmacokinetics, pharmacogenetics, and drug inter actions was used to identify pertinent literature. DATA SYNTHESIS: The pharmacokinetic profiles of selected antidepressants are reviewed and the impact of hepatic microsomal enzymes on antidepressant metabolism is considered. How phenotypic differences influence the metabolism of antidepressant drug therapy is addressed. To evaluate the clinical im plications of these pharmacokinetic and pharmacogenetic considerations , the findings of studies designed to elucidate drug interactions invo lving antidepressant agents are discussed. CONCLUSIONS: Differences in antidepressant plasma concentrations, and possibly safety, are caused by polymorphism in the genes that encode some of the cytochrome P450 isoenzymes that metabolize antidepressants. The isoenzymes 1A2, 2C9/19 , 2D6, and 3A4 are the major enzymes that catalyze antidepressant meta bolic reactions. Antidepressants can be tither substrates or inhibitor s of these enzymes, which also metabolize many other pharmacologic age nts. Although the cytochrome enzymes that metabolize antidepressants h ave not been fully characterized, interaction profiles of the newer an tidepressants are becoming more clearly defined. Determining patient p henotypes is not practical in the clinical setting, but an awareness o f the possibility of genetic polymorphism in antidepressant metabolism may help explain therapeutic failure or toxicity, help predict the li kelihood of drug interactions, and help clinicians better manage antid epressant drug therapy.