Sex differences in the pharmacokinetics of pioglitazone in rats

Clinical studies have suggested that pioglitazone, an insulin sensitizer, has a stronger effect in women than in men. To determine the sex difference in the pharmacokinetics of pioglitazone, we examined the plasma and white adipose tissue levels of pioglitazone and its active metabolites (M-II, M-III and M-IV) in male and female rats treated with a single or repeated oral administration of pioglitazone (10 mg/kg). The AUCs of pioglitazone (149.6 +/- 22.6 vs. 103.3 +/- 14.0 mug.h/ml; P<0.01), M-III (31.4 +/- 8.1 vs. 20.2 +/- 4.7 mug.h/ml; P<0.05) and M-IV (41.9 +/- 15.5 vs. 14.1 +/- 1.6 mug.h/ml; P<0.01) were larger in female rats than in male rats, but the levels of M-II were similar. Any of the compounds did not accumulate in plasma after repeated administration. According to kinetic model analysis, the apparent elimination rate of pioglitazone and the formation rate of M-II were faster in male rats than in female rats. No significant sex difference was found in the tissue-to-plasma concentration ratios of pioglitazone or its active metabolites in white adipose tissue. These results suggest that there are sex differences in the plasma levels of pioglitazone and some of its active metabolites and that those differences are reflected in differences in white adipose tissue levels. (C) 2003 Elsevier Inc. All rights reserved.