Umehara K-I, Nakamata T, Suzuki K, Noguchi K, Usui T, Kamimura H
Drug Metabolism Research Laboratories, Drug Discovery Research, Astellas Pharma Inc., Tokyo, Japan.
Eur J Drug Metab Pharmacokinet. 2008 Apr-Jun;33(2):117-27. doi: 10.1007/BF03191028.
The pharmacokinetics of YM758, a novel funny If current channel (If channel) inhibitor, was investigated after single intravenous (i.v.) and oral dosing to rats and dogs, and partially compared with the results in humans by using liver microsomes. After i.v. administration, the plasma YM758 concentrations decreased, with an elimination half-life (t(1/2)) of 1.14-1.16 h in rats and 1.10-1.30 h in dogs. Total body clearance (CL(tot)) was 5.71-7.27 and 1.75-1.90 L/h/kg in rats and dogs, respectively which was comparable to the hepatic blood flow rate. In dogs, the pharmacokinetic profiles for i.v. bolus administration and continuous infusion did not differ. After oral administration, the levels of YM758 in rat plasma increased more than dose-proportionally, whereas almost linear pharmacokinetics were observed in dogs. Absolute bioavailability was 7.5%-16.6% in rats and 16.1%-22.0% in dogs. The plasma protein binding saturation of YM758 was observed in dogs and humans; this finding is consistent with the result that the major binding protein of YM758 in plasma is alpha1-acid glycoprotein (AGP), in particular in humans. The blood-to-plasma partition coefficient values were 1.36-1.42 in rats, 0.95-1.15 in dogs and 0.71-0.85 in humans. The results of the metabolic study on liver microsomes indicated that the non-linear pharmacokinetics of YM758 observed in rats may be partially due to a first-pass effect in the gastrointestinal tract and the liver.
新型If电流通道（If通道）抑制剂YM758在大鼠和犬单次静脉注射及口服给药后进行了药代动力学研究，并通过使用肝微粒体部分地与人体研究结果进行了比较。静脉注射给药后，大鼠血浆中YM758浓度下降，消除半衰期（t(1/2)）在大鼠中为1.14 - 1.16小时，在犬中为1.10 - 1.30小时。大鼠和犬的总体清除率（CL(tot)）分别为5.71 - 7.27和1.75 - 1.90 L/h/kg，这与肝血流量相当。在犬中，静脉推注给药和持续输注的药代动力学曲线无差异。口服给药后，大鼠血浆中YM758水平的增加超过剂量比例，而在犬中观察到几乎呈线性的药代动力学。大鼠的绝对生物利用度为7.5% - 16.6%，犬为16.1% - 22.0%。在犬和人体中观察到YM758的血浆蛋白结合饱和；这一发现与YM758在血浆中的主要结合蛋白是α1 - 酸性糖蛋白（AGP）的结果一致，特别是在人体中。大鼠的血 - 血浆分配系数值为1.36 - 1.42，犬为0.95 - 1.15，人体为0.71 - 0.85。肝微粒体代谢研究结果表明，在大鼠中观察到的YM758非线性药代动力学可能部分归因于胃肠道和肝脏的首过效应。
