CLINICAL IMPLICATIONS OF DOSE-DEPENDENT CYTOCHROME-P-450 DRUG-DRUG INTERACTIONS WITH ANTIDEPRESSANTS

The magnitude of drug-drug interactions in vitro involving competitive inhibition of cytochrome (CYP) isozymes by newer antidepressants can theoretically be shown to be dependent upon several factors. These inc lude the concentration of both the substrate and inhibitor, the affini ty of the inhibitor for the inhibited isozyme, and an inhibition const ant. The purpose of this study was to compare the results from three h uman drug interaction studies with theoretical considerations and the results from in vitro studies. Of special interest was the relationshi p between dose or concentration of an enzyme inhibitor and the change in the plasma concentration of a co-administered drug. Observed data w ere fit to equations using linear regression and nonlinear least squar es regression analysis. All three human data sets demonstrated a linea r dose or concentration dependency in the magnitude of the observed dr ug-drug interaction. The results draw attention to the dose dependent nature of drug-drug interactions. As the dose of antidepressant is und er clinician control, guidelines are suggested to minimize the clinica l impact of antidepressant drug interactions. (C) 1998 John Wiley & So ns, Ltd.