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 microg.h/ml; P<0.01), M-III (31.4+/-8.1 vs. 20.2+/-4.7 microg.h/ml; P<0.05) and M-IV (41.9+/-15.5 vs. 14.1+/-1.6 microg.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.

译文

临床研究表明,胰岛素增敏剂吡格列酮对女性的作用强于男性。为了确定吡格列酮的药代动力学的性别差异,我们检查了吡格列酮及其活性代谢物 (m-ii,M-III和M-IV) 在单次或重复口服吡格列酮 (10 mg/kg) 治疗的雄性和雌性大鼠中。吡格列酮的auc (149.6 +/-22.6对103.3 +/-14.0微g.h/ml; P<0.01),M-III (31.4 +/-8.1对20.2 +/-4.7微g.h/ml; P<0.05) 和M-IV (41.9 +/-15.5 vs. 14.1 +/-1.6 microg.h/ml; P<0.01) 在雌性大鼠中大于雄性大鼠,但M-II的水平相似。重复给药后,任何化合物均未在血浆中积累。根据动力学模型分析,雄性大鼠吡格列酮的表观消除率和M-II的形成速率均快于雌性大鼠。在白色脂肪组织中吡格列酮或其活性代谢物的组织与血浆浓度比中未发现明显的性别差异。这些结果表明,吡格列酮及其某些活性代谢物的血浆水平存在性别差异,这些差异反映在白色脂肪组织水平的差异上。

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