Effect of Cimetidine on the Pharmacokinetics of Fentiazac in Rats

The effect of cimetidine (CM) on the pharmacokinetics of fentiazac (FT) was studied in six rats. FT was administered by intravenous (iv) bolus injection at doses of 5, 10, and 20 mg/kg to rats receiving iv infusion of saline (control) or CM. The infusion of CM was conducted to achieve steady-state plasma concentrations (Css) of CM of 30 and 60 μg/mL. In the control rats, the plasma disposition of FT and its major metabolite, p-hydroxy FT, followed a classical drug-metabolite profile irrespective of FT dose. The plasma level of p-hydroxy FT was comparable with that of FT. The disappearance of FT from the rat plasma was significantly delayed by the CM infusion, and p-hydroxy FT was undetectable in the plasma in CM-treated rats. The total body clearance (CLt of FT was decreased to 20–50% of the control value in CM-treated rats, implying that FT metabolism to p-hydroxy FT is almost completely impaired by CM. The CLt values in rats with different Css of CM (30 and 60 μg/mL) were not significantly different from each other. The distribution volume of FT at steady state (Vdss) was decreased to 60–70% of the control value by the CM infusion at higher doses of FT (10 and 20 mg/kg). The decreases in Vdss and CLt seem not to be related to the binding of FT to plasma protein because the binding of FT was not influenced by CM. In clinical settings, the magnitude of the pharmacokinetic difference may warrant dose adjustment to avoid toxic effects of FT when administered with CM.