Knipe Jay O, Mosure Kathleen W
Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Research Institute, Wallingford, CT 06492, USA.
Biopharm Drug Dispos. 2008 Jul;29(5):270-9. doi: 10.1002/bdd.612.
The phosphate ester, BMS-292655, was developed as a water-soluble prodrug of the antifungal agent, ravuconazole (BMS-207147). BMS-292655 was comparatively stable in rat, beagle dog, cynomolgus monkey and human plasma, but was hydrolysed upon incubation with liver S9 preparations from all species. The major product in rat, monkey and human S9 was BMS-207147, while in dog S9, the intermediate ester, BMS-300043, predominated. BMS-300043 itself was more stable in dog S9 than in S9 preparations from the other species. Intravenous administration of BMS-292655 to rats, beagle dogs and cynomolgus monkeys indicated species differences in the extent of formation of BMS-207147 (monkeys>rats>dogs). The lower overall generation of BMS-207147 in dogs was consistent with the presence of circulating plasma levels of BMS-300043. BMS-300043 was present in monkey plasma but not detectable in rat plasma. The conversion of BMS-292655 to BMS-207147 in the presence of human S9 indicated the potential for BMS-292655 to function as a BMS-207147 prodrug in humans. The similarity in the hydrolysis of BMS-292655 when incubated with human and monkey S9 in vitro, coupled with the effective release of BMS-207147 from BMS-292655 upon i.v. administration to monkeys, is consistent with this conclusion.
磷酸酯BMS - 292655是作为抗真菌药物雷夫康唑（BMS - 207147）的水溶性前药而研发的。BMS - 292655在大鼠、比格犬、食蟹猴和人血浆中相对稳定，但与所有物种的肝脏S9制剂孵育时会发生水解。大鼠、猴和人S9中的主要产物是BMS - 207147，而在犬S9中，中间酯BMS - 300043占主导。BMS - 300043本身在犬S9中比在其他物种的S9制剂中更稳定。对大鼠、比格犬和食蟹猴静脉注射BMS - 292655表明，在BMS - 207147的形成程度上存在物种差异（猴>大鼠>犬）。犬体内BMS - 207147的总体生成量较低与循环血浆中BMS - 300043的存在一致。BMS - 300043存在于猴血浆中，但在大鼠血浆中无法检测到。在人S9存在的情况下，BMS - 292655向BMS - 207147的转化表明BMS - 292655在人体内有作为BMS - 207147前药发挥作用的潜力。BMS - 292655在体外与人及猴S9孵育时水解情况相似，再加上静脉注射给猴后BMS - 207147能从BMS - 292655有效释放，这与该结论一致。
