KINETIC INTERACTIONS OF LIDOCAINE, DIPHENHYDRAMINE, AND VERAPAMIL WITH DILTIAZEM - A STUDY USING ISOLATED-PERFUSED RAT-LIVER

The effect of several tertiary amines, which are known enzyme inhibito rs, 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 sha rp increase in the perfusate concentration of DZ, which was followed b y a decline to a new steady-state concentration (C-nss) that was highe r than the original C-nss value (46 and 45%, respectively). The initia l sharp increase in DZ concentration was attributed to the displacemen t of DZ from its tissue binding sites; the higher C-ss values were due to the inhibition of N-oxidation and O-demethylation, and some unknow n primary metabolic pathways. The kinetics of LID were altered by DZ; the steady-state extraction ratio of LID was reduced and the character istic maximum in the concentration-time profile of its N-deethylated m etabolite, 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 ina ctivation on DZ disposition was evaluated by intraperitoneal pretreatm ent 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 fo r at least 3 days. Pretreatment with each of these drugs did not chang e the extraction ratio, hepatic clearance, and time to achieve steady state of DZ significantly, however, pretreatment with DZ and LID incre ased the steady-state concentrations of the deacetyl and N- and O-deme thyl metabolites of DZ, resulting in a higher material balance (89.0 /- 8.9 and 88.4 +/- 19.4 vs. 65.9 +/- 6.9%, p > 0.05).