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 include the concentration of both the substrate and inhibitor, the affinity of the inhibitor for the inhibited isozyme, and an inhibition constant. The purpose of this study was to compare the results from three human drug interaction studies with theoretical considerations and the results from in vitro studies. Of special interest was the relationship between dose or concentration of an enzyme inhibitor and the change in the plasma concentration of a co-administered drug. Observed data were fit to equations using linear regression and nonlinear least squares regression analysis. All three human data sets demonstrated a linear dose or concentration dependency in the magnitude of the observed drug–drug interaction. The results draw attention to the dose dependent nature of drug–drug interactions. As the dose of antidepressant is under clinician control, guidelines are suggested to minimize the clinical impact of antidepressant drug interactions. © 1998 John Wiley & Sons, Ltd.