Rosiglitazone Trimethoprim

Similar studies have shown increased plasma concentrations of rosiglitazone after the addition of ketocona-zole (144) and trimethoprim (145). 

Rosiglitazone is mainly metabolized by the CYP2C8, and CYP2C9 has a minor role. Trimethoprim is a competitive inhibitor of CYP2C8 and it increases rosiglitazone concentrations, with increased risks of peripheral edema and pulmonary edema. Genotype may influence the ability of trimethoprim to inhibit CYP2C8 (147). 

Niemi M, Backman JT, Neuvonen PJ. Effects of trimethoprim and rifampicin on the pharmacokinetics of the cytochrome P450 2C8 substrate rosiglitazone. Clin Pharmacol Ther 2004 76 239 19. 

Hruska MW, Amico JA, Langaee TY, Ferrell RE, Fitzgerald SM, Frye RF. The effect of trimethoprim on CYP2C8 mediated rosiglitazone metabolism in human liver microsomes and healthy subjects. Br J Clin Pharmacol 2005 59 70-9. 

Trimethoprim increases the AUC of repaglinide and would be expected to increase its effects in some patients. The effect of trimethoprim on the AUC of rosiglitazone is more modest and less likely to be clinically relevant. Trimethoprim does not appear to significantly affect the pharmacokinetics of intravenous tolbutamide. 

In a study in 10 healthy subjects trimethoprim 160 mg twice daily for 4 days increased the AUC of a single 4-mg dose of rosiglitazone given on day 3 by 37%. The half-life of rosiglitazone was increased by 26% but the peak plasma level was only slightly affected (14% inerease). Similarly, in another study, trimethoprim 200 mg twiee daily for 5 days increased the AUC ofa single 8-mg dose of rosiglitazone by 31% and increased the half-life by 27% ... 

The more modest increase in AUC of rosiglitazone is less likely to be clinically important, but, until more experience is gained, some caution is warranted. No interaction would be expeeted between trimethoprim and tolbutamide, although note that co-trimoxazole has rarely caused hypogly-caemia alone or combined with various sulphonylureas, see Antidiabetics + Sulfonamides , p.506. 

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