The effect of trimethoprim on CYP2C8 mediated rosiglitazone metabolism in human liver microsomes and healthy subjects

Abstract

Aims: 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 shown in vitro to be a selective inhibitor of CYP2C8. The purpose of this study was to evaluate the effect of trimethoprim on the CYP2C8 mediated metabolism of rosiglitazone in vivo and in vitro.

Methods: The effect of trimethoprim on the metabolism of rosiglitazone in vitro was assessed in pooled human liver microsomes. The effect in vivo was 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.

Results: Trimethoprim inhibited rosiglitazone metabolism both in vitro and in vivo. Inhibition of rosiglitazone para-hydroxylation by trimethoprim in vitro was found to be competitive with apparent K(i) and IC(50) values of 29 microm and 54.5 microm, respectively. In the presence of trimethoprim, rosiglitazone plasma AUC was increased by 31% (P = 0.01) from 2774 +/- 645 microg l(-1) h to 3643 +/- 1051 microg 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.

Conclusions: These results indicate that trimethoprim is a competitive inhibitor of CYP2C8-mediated rosiglitazone metabolism in vitro and that trimethoprim administration increases plasma rosiglitazone concentrations in healthy subjects.

Figure 1

Mean (±SD) log concentration vs. time profile of rosiglitazone in the presence (closed triangles) and absence (closed squares) of trimethoprim, 200 mg given twice daily for five days. Data are from eight healthy subjects. Control (▪), trimethoprim (▴)

Figure 2

Rosiglitazone (A) AUC and (B) t_1/2 in the presence (Trimethoprim) and absence (Control) of trimethoprim, 200 mg given twice daily for five days to eight healthy subjects. Solid lines indicate the wild type genotype (CYP2C8*1/*1) and dotted lines indicate the heterozygous genotype (CYP2C8*1/*2 or CYP2C8*1/*3)

Figure 3

Relationship between the fold increase in rosiglitazone AUC and the trimethoprim Css_ave concentration. The linear regression line is based on data from subjects having the CYP2C8*1/*1 or *1/*2 genotype (▪; r² = 0.97, P = 0.0021). The relationship was not significant when subjects with the CYP2C8*1/*3 genotype (▿) were included (r² = 0.08, P = 0.48)

Figure 4

Rosiglitazone para-hydroxylation by human liver microsomes expressed as a percentage of control in the presence of (A) trimethoprim and (B) gemfibrozil. Arrows indicate (A) Css_max for trimethoprim administered 200 mg twice daily, which was determined in the present study, and (B) Css_max for gemfibrozil administered 600 mg twice daily, taken from [18]