Diazepam Metabolism in Kidney of Male and Female Rats of Varying Strain

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Previously, we have reported drastic strain differences of diazepam metabolism in the liver of varying rat strain. In this study, to characterize strain and sex differences of diazepam metabolism in the kidney, renal microsomal diazepam metabolic activities have been determined in the rat strains of Dark Agouti (DA), Sprague-Dawley (SD), Brown Norway (BN) and Wistar (WS). We found that the major pathway of diazepam metabolism in kidney was diazepam N-demethylation, differently from 3-hydrozylation in liver. The dose-course (12.5～200 μM of diazepam) study revealed that DA and WS male rats had higher activity in diazepam N-demethylation than those of SD and BN rats. In contrast to male, a lower activity of diazepam N-demethylation was observed in female BN rats. By Western blot analysis, constitutive protein expressions of cytochrome P450 (CYP) 2C11, responsible for diazepam N-demethylation, were detected in four strain of both male and female rats and BN rats had lower expression level of CYP2C11 protein. However, we did not observed significant differences in the kinetic parameters of diazepam N-demethylation. Our results suggested that there was strain difference in CYP-dependent diazepam N-demethylation in rat kidney, differently from that in liver microsomes.