In this study, we elucidated the plasma pharmacokinetics of MP and its metabolites in male rats after an oral administration. MPOL is most likely to be produced by 11β-HSD1 in the male rats and humans.

Administration of cadmium (Cd) at a dose of 1.23 mg/kg (2.0 mg/kg as CdCl(2)) markedly decreased the activity of an enzyme (acetohexamide reductase) catalysing the ketone-reduction of acetohexamide, an oral antidiabetic drug, in liver microsomes of male rats. However, the decreased enzyme activity was increased by repeated treatment with testosterone propionate (TP). When male rats were castrated and TP was given to the castrated ones, a similar decrease and increase, as described above, were observed in the microsomal enzyme activity. Cd exposure to male rats induced haemorrhage and atrophy of the testes and significantly diminished serum testosterone levels. There was no possibility that Cd accumulated in liver microsomes of male rats causing direct inhibition of the microsomal enzyme activity. We conclude that Cd exposure decreases androgen-dependent metabolism of acetohexamide in liver microsomes of male rats through its testicular toxicity. Cd exposure had no effect on acetohexamide reductase activity in liver cytosol of male rats.

The influence of aging on the reductase activity of acetohexamide, an oral antidiabetic drug with a ketone group, was examined in liver microsomes and cytosol of male rats. Acetohexamide reductase activities in liver microsomes of male rats at 26 and 31 months of age were much lower than that in liver microsomes of male rats at 9 weeks of age. Testectomy markedly decreased acetohexamide reductase activity in liver microsomes of the 9-week old rats and the decreased enzyme activity was significantly increased by testosterone administration. These results indicate, at least in part, that aging decreases the enzyme activity by decreasing the secretion of testosterone from the testes. On the other hand, aging (26 months of age) did not affect acetohexamide reductase activity in liver cytosol of male rats, although the enzyme activity at 31 months of age was slightly but significantly lower than that in liver cytosol of male rats at 9 weeks of age. Testectomy or testosterone administration had no effect on the enzyme activity in liver cytosol of 9-week old male rats.

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