Differential Pharmacokinetics of Acetohexamide in Male Wistar-Imamichi and Sprague-Dawley Rats: Role of Microsomal Carbonyl Reductase

Abstract

Acetohexamide (AH) is reduced to its alcohol metabolite by carbonyl reductase. We have previously shown that carbonyl reductase present in the liver microsomes of rats is a male-specific and androgen-dependent enzyme. In the present study, the role of microsomal carbonyl reductase in the pharmacokinetics of AH was examined in male Wistar-Imamichi (WI) and Sprague-Dawley (SD) rats after its intravenous administration. AH was eliminated more slowly from plasma in the WI strain, which lacks most of the microsomal carbonyl reductase, than in the SD strain. Furthermore, several pharmacokinetic parameters were derived from the data for the plasma concentrations of AH. The plasma clearance (CL(p)) of AH (72.8+/-11.2 ml/h/kg) in male WI rats was significantly smaller than that (105.5+/-11.1 ml/h/kg) in male SD rats. Testectomy caused a marked decrease, from 105.5+/-11.1 to 44.3+/-11.8 ml/h/kg, in the CL(p) of AH in male SD rats. These results indicate that microsomal carbonyl reductase plays a critical role in the differential pharmacokinetics of AH in male WI and SD rats.