抗乙肝新药阿米福韦药代动力学研究

Phamacokinetics of Novel Antr-HBV Prodrug MCC-478

目的对抗乙肝病毒前药阿米福韦(MCC-478)在比格犬中的口服生物利用度及体外的代谢转化情况进行研究。方法比格犬分别经灌胃和静脉注射给予等克分子量MCC-478和其活性产物602076,采用ESI-LC-MS/MS技术同时定量检测比格犬血浆中MCC-478和602076。体外MCC-478或602076分别在比格犬血浆、肝匀浆和肠匀浆等孵育体系,于不同时间点取样,采用ESI-LC-MS/MS技术同时定量检测比格犬血浆和肝肠匀浆中MCC-478和602076浓度。结果比格犬经灌胃给予MCC-478后体内602076的绝对生物利用度较低(2.38%)。在体外孵育体系中,MCC-478在犬血浆、肝匀浆和肠匀浆中均有代谢降解,t1/2分别为10.76、11.20、59.23 min,仅在血浆孵育体系中检测到活性产物602076且代谢活化率较低(5.90%)。602076在肝匀浆和肠匀浆中均较稳定,t1/2分别为533.08、693.00 min。结论比格犬灌胃MCC-478后,602076在比格犬体内的口服生物利用度较低可能与其体外代谢活化效率低有关。

Objective To fine nucleotide analogue prodrug study the bioavailability and the metabolic conversion in vitro of MCC-478, a pu- which can anti-HBV, in Beagle dogs. Methods Pharmacokinetic parameters were determined for 602076 following intravenous and oral administration of 602076 and MCC-478, respectively, MCC- 478 or 602076 was incubated with dog plasma, small intestinal and liver homogenates of male Beagle dogs. Plasma and tissue homogenates concentrations of MCC-478 and 602076 were quantitated with a validated LC-MS/MS as- say. Results The overall absolute oral bioavailability of 602076 from MCC-478 was determined to be 2.83% in male Beagle dogs. The metabolism of MCC-478 in plasma, liver and small intestinal homogenates were similar, all hy- drolysised, their t 1/2 were 10.76,11.20,59.23 min, respectively ; however, the active product 602076 was only ob- served in plasma fraction, which exhibited low transformation ratio （5.90%）. On the contrast, 602076 was nearly steady both in liver and intestine homogenates, t 1/2 were 533.08,693.00 min, respectively. Conclusion Given the transformation ratio, the limited in vitro conversion of MCC-478 to 602076 in plasma is probably consistent with the low absolute bioavailability of 602076 from MCC-478.