In vitro protein binding studies with BMS-204352: Lack of protein binding displacement interaction in human serum

BMS-204352, a maxi-K channel opener, is currently under development for the treatment of stroke. Protein binding of BMS-204352 was determined in sera from several species, namely, rat, monkey, dog, and human. Data indicated t hat the compound was shown to be highly protein bound in serum from all spe cies (ca. 99.6%). In order to test for the potential for drug-drug interact ions and competitive displacement of BMS-204352 by diazepam, phenytoin, pro pranolol, and warfarin, in vitro experiments were performed using spiked hu man serum and ex vivo human plasma samples. Protein binding was determined using equilibrium dialysis for 4h at maximal therapeutic concentrations for each drug alone or in appropriate combination in spiked serum samples. Ex vivo samples from a clinical BMS-204352 study (0, 1, and 24 h) were dialyze d separately after addition of diazepam, phenytoin, propranolol, or warfari n. Drug content in biological matrices was measured for radioactivity using liquid scintillation counting. Results indicated that (1) addition of diaz epam, phenytoin, propranolol, or warfarin did not alter the free fraction o f BMS-204352; (2) BMS-204352 did not displace diazepam, phenytoin, proprano lol, or warfarin from their protein binding sites, and (3) comparison of ex vivo plasma samples after BMS-204352 dosing indicated no impact of BMS-204 352 and/or its metabolites on the free fraction of diazepam, phenytoin, pro pranolol, or warfarin. In conclusion, the potential for a drug-drug interac tion due to alterations in protein binding with BMS-204352 is unlikely. Cop yright (C) 2001 John Wiley & Sons, Ltd.