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The effect of trimethoprim on CYP2C8 mediated rosiglitazone metabolism in human liver microsomes and healthy subjects
Author(s) -
Hruska M. W.,
Amico J. A.,
Langaee T. Y.,
Ferrell R. E.,
Fitzgerald S. M.,
Frye R. F.
Publication year - 2005
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2005.02263.x
Subject(s) - rosiglitazone , pharmacology , trimethoprim , cyp2c8 , medicine , endocrinology , microsome , pharmacokinetics , chemistry , cytochrome p450 , in vitro , diabetes mellitus , metabolism , antibiotics , biochemistry , cyp3a4
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 µ m and 54.5 µ m , respectively. In the presence of trimethoprim, rosiglitazone plasma AUC was increased by 31% ( P = 0.01) from 2774 ± 645 µg l −1 h to 3643 ± 1051 µg 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.