Ueda K, Yamaoka K, Rodriguez M E, Shibukawa A, Nakagawa T
Faculty of Pharmaceutical Sciences, Kyoto University, Japan.
Drug Metab Dispos. 1997 Mar;25(3):281-6.
The enantioselective local disposition of semotiadil (R-enantiomer) and levosemotiadil (S-enantiomer) in rat liver was investigated in the single-pass perfusion system containing 1% bovine serum albumin (BSA). After an instantaneous injection of semotiadil, levosemotiadil, or Evans Blue (a marker of BSA), each outflow time profile from the liver was analyzed by a two-compartment dispersion model. The recovery ratio, FH (1.88 +/- 0.28%), of semotiadil was significantly smaller than that (8.99 +/- 1.40%) of levosemotiadil. The mean transit time, fH (0.146 +/- 0.014 min) of semotiadil was significantly smaller than that (0.191 +/- 0.012 min) of levosemotiadil. The biliary excretion kinetics of these enantiomers was also evaluated by moment analysis. The parent compound (semotiadil or levosemotiadil) was not detected in bile, but four metabolites generated from each parent enantiomer were found in the bile. A portion (16.5 +/- 1.2%) of the drug eliminated by the liver was recovered as R-metabolites in the bile within 1 hr after an injection of semotiadil, whereas 11.2 +/- 1.6% was recovered as S-metabolites in the bile within 1 hr after an injection of levosemotiadil. This excreted percentage into the bile was significantly different between R- and S-metabolites. The mean biliary excretion time MRTe (19.1 +/- 2.2 min) of total R-metabolites was significantly larger than that (14.8 +/- 1.1 min) of total S-metabolites. In conclusion, stereo-selectivity was suggested both at the hepatic elimination of the parent compound and at the biliary excretion of the metabolites.
在含有1%牛血清白蛋白（BSA）的单通道灌注系统中，研究了司莫替地尔（R-对映体）和左司莫替地尔（S-对映体）在大鼠肝脏中的对映选择性局部处置情况。在瞬间注射司莫替地尔、左司莫替地尔或伊文思蓝（BSA的一种标志物）后，通过双室扩散模型分析肝脏的每个流出时间曲线。司莫替地尔的回收率FH（1.88±0.28%）显著低于左司莫替地尔的回收率（8.99±1.40%）。司莫替地尔的平均通过时间fH（0.146±0.014分钟）显著短于左司莫替地尔的平均通过时间（0.191±0.012分钟）。还通过矩分析评估了这些对映体的胆汁排泄动力学。在胆汁中未检测到母体化合物（司莫替地尔或左司莫替地尔），但在胆汁中发现了由每种母体对映体产生的四种代谢物。注射司莫替地尔后1小时内，肝脏消除的药物中有一部分（16.5±1.2%）以R-代谢物的形式在胆汁中回收，而注射左司莫替地尔后1小时内，有11.2±1.6%以S-代谢物的形式在胆汁中回收。R-和S-代谢物进入胆汁的排泄百分比有显著差异。总R-代谢物的平均胆汁排泄时间MRTe（19.1±2.2分钟）显著长于总S-代谢物的平均胆汁排泄时间（14.8±1.1分钟）。总之，在母体化合物的肝脏消除和代谢物的胆汁排泄方面均显示出立体选择性。
