Differences in the Pharmacokinetics of 4-Amino-3-Chlorophenyl Hydrogen Sulfate, a Metabolite of Resatorvid, in Rats and Dogs
Differences in the Pharmacokinetics of 4-Amino-3-Chlorophenyl Hydrogen Sulfate, a Metabolite of Resatorvid, in Rats and Dogs
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DOI：
10.1124/dmd.111.043729
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发表时间：
2012-04-01
影响因子：
3.9
通讯作者：
Asahi, Satoru
中科院分区：
文献类型：
--
作者：
Jinno, Fumihiro;Takeuchi, Toshiyuki;Asahi, Satoru
采用放射性标记M-III （[(14C)]M-III）研究了瑞托维中4-氨基-3-氯苯基硫酸氢M-III在大鼠和狗体内的药代动力学。给大鼠和狗静脉注射0.5 mg/kg的[C-14]M-III后，大鼠血浆中C-14的消除半衰期约为狗的1/30。M-III在体内和体外的血浆蛋白结合率均较高，且在两种动物中相同。M-III在大鼠体内的内在清除率（CLint）远高于肾小球滤过率。大鼠肾脏中的[C-14]M-III浓度远高于血浆中的浓度。相反，在狗的肾脏中，[C-14]M-III的浓度远低于血浆中的浓度。这些结果表明，M-III在大鼠体内被有效地吸收进入肾脏，并进入尿液排泄；然而，在狗中，推测M-III的肾脏摄取无效。[C-14]M-III与丙戊酸同时持续静脉给药大鼠时，M-III的CLint随丙戊酸血浆浓度的增加而降低，说明丙戊酸抑制了大鼠肾脏对M-III的摄取。也有人认为，基底外膜中有机阴离子运输系统的摄取参与了大鼠肾对M-III的摄取。M-III在大鼠和狗之间的药代动力学差异被认为主要是由于尿经肾分布过程排泄的差异造成的。
The pharmacokinetics of 4-amino-3-chlorophenyl hydrogen sulfate, M-III of resatorvid, in rats and dogs were investigated using radiolabeled M-III ([(14C)]M-III). The elimination half-life of C-14 in the plasma of rats was approximately 1/30 of that of dogs after intravenous dosing of [C-14]M-III at 0.5 mg/kg to rats and dogs. The in vitro and in vivo plasma protein binding ratios of M-III were relatively high and were the same in both species. The intrinsic clearance (CLint) of M-III in rats was much higher than the glomerular filtration rate in rats. Furthermore, the concentration of [C-14]M-III in the kidney of rats was much higher than that in the plasma. On the contrary, in dogs, the concentration of [C-14]M-III in the kidney was very much lower than that in the plasma. These results indicated that M-III was effectively taken up into the kidney and was excreted into the urine in rats; however, in dogs, ineffective renal uptake of M-III was presumed. When [C-14]M-III and probenecid were simultaneously and continually infused intravenously to rats, the CLint of M-III decreased with increasing plasma concentrations of probenecid, indicating that kidney uptake of M-III in rats was inhibited by probenecid. It was also thought that uptake by the organic anion transport system(s) in the basolateral membrane is involved in the renal uptake of M-III in rats. The pharmacokinetic differences of M-III between rats and dogs are considered to be mainly caused by the difference in the urinary excretion via the renal distribution processes.