trimethoprim and sulfamethoxazole are selective inhibitors of cyp2c8 and cyp2c9 respectively to evaluate the inhibitory effects of trimethoprim and sulfamethoxazole on cytochrome p450 p450 isoforms selective marker reactions for cyp1a2 cyp2a6 cyp2c8 cyp2c9 cyp2c19 cyp2d6 cyp2e1 and cyp3a4 were examined in human liver microsomes and recombinant cyp2c8 and cyp2c9 the in vivo drug interactions of trimethoprim and sulfamethoxazole were predicted in vitro using ii ki values with concentrations ranging from 5 to 100 microm trimethoprim exhibited a selective inhibitory effect on cyp2c8mediated paclitaxel 6alphahydroxylation in human liver microsomes and recombinant cyp2c8 with apparent ic50 ki values of 54 microm 32 microm and 75 microm respectively with concentrations ranging from 50 to 500 microm sulfamethoxazole was a selective inhibitor of cyp2c9mediated tolbutamide hydroxylation in human liver microsomes and recombinant cyp2c9 with apparent ic50 ki values of 544 microm 271 microm and 456 microm respectively with concentrations higher than 100 microm trimethoprim and 500 microm sulfamethoxazole both drugs lost their selectivity for the p450 isoforms based on estimated total hepatic concentrations or free plasma concentrations of the drugs and the scaling model one would expect in vivo in humans 80 26 and 13 24 inhibition of the metabolic clearance of cyp2c8 and cyp2c9 substrates by trimethoprim and sulfamethoxazole respectively in conclusion trimethoprim and sulfamethoxazole can be used as selective inhibitors of cyp2c8 and cyp2c9 in in vitro studies in humans trimethoprim and sulfamethoxazole may inhibit the activities of cyp2c8 and cyp2c9 respectively