Abstract

The effect of several tertiary amines, which are known enzyme inhibitors, on the disposition of diltiazem (DZ) was evaluated using a single-pass isolated rat liver perfusion system. Coinfusion of lidocaine (LID) or diphenhydramine (DPH) at the steady state of DZ resulted in a sharp increase in the perfusate concentration of DZ, which was followed by a decline to a new steady-state concentration (Cnss) that was higher than the original Cnss value (46 and 45%, respectively). The initial sharp increase in DZ concentration was attributed to the displacement of DZ from its tissue binding sites; the higher Css values were due to the inhibition of N-oxidation and O-demethylation, and some unknown primary metabolic pathways. The kinetics of LID were altered by DZ; the steady-state extraction ratio of LID was reduced and the characteristic maximum in the concentration-time profile of its N-deethylated metabolite, MEGX, was abolished. These results suggest that DZ and LID share common isozymes in their disposition and that the two drugs are also capable of inactivating similar enzymes. The effect of enzyme inactivation on DZ disposition was evaluated by intraperitoneal pretreatment of rats with either saline (0.4 ml) or 1 of the 4 drugs--DZ (20 mg/kg), LID (30 mg/kg), DPH (20 mg/kg), and verapamil (10 mg/kg)--daily for at least 3 days.(ABSTRACT TRUNCATED AT 250 WORDS)