부산대학교 도서관

Rosiglitazone, a thiazolidinedione antidiabetic medication used in the treatment of Type 2 diabetes mellitus, is predominantly metabolized by the cytochrome P450 (CYP) enzyme CYP2C8. The anti-infective drug trimethoprim has been shownin vitroto be a selective inhibitor of CYP2C8. The purpose of this study was to evaluate the effect of trimethoprim on the CYP2C8 mediated metabolism of rosiglitazonein vivoandin vitro.The effect of trimethoprim on the metabolism of rosiglitazonein vitrowas assessed in pooled human liver microsomes. The effectin vivowas determined by evaluating rosiglitazone pharmacokinetics in the presence and absence of trimethoprim. Eight healthy subjects (four men and four women) completed a randomized, cross-over study. Subjects received single dose rosiglitazone (8 mg) in the presence and absence of trimethoprim 200 mg given twice daily for 5 days.Trimethoprim inhibited rosiglitazone metabolism bothin vitroandin vivo. Inhibition of rosiglitazonepara-hydroxylation by trimethoprimin vitrowas found to be competitive with apparentKi and IC50 values of 29µmand 54.5µm, respectively. In the presence of trimethoprim, rosiglitazone plasma AUC was increased by 31% (P = 0.01) from 2774 ± 645µg l−1 h to 3643 ± 1051µg l−1 h (95% confidence interval (CI) for difference 189, 1549), and half-life was increased by 27% (P = 0.006) from 3.3 ± 0.5 to 4.2 ± 0.8 h (95% CI for difference 0.36, 1.5). Trimethoprim reduced the para-O-sulphate rosiglitazone/rosiglitazone and the N-desmethylrosiglitazone/rosiglitazone AUC(0–24) ratios by 22% and 38%, respectively.These results indicate that trimethoprim is a competitive inhibitor of CYP2C8-mediated rosiglitazone metabolismin vitroand that trimethoprim administration increases plasma rosiglitazone concentrations in healthy subjects. [ABSTRACT FROM AUTHOR]