Abstract

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,F_H (1.88 ± 0.28%), of semotiadil was significantly smaller than that (8.99 ± 1.40%) of levosemotiadil. The mean transit time, t̄_H (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 betweenR- and S-metabolites. The mean biliary excretion time MRTe (19.1 ± 2.2 min) of totalR-metabolites was significantly larger than that (14.8 ± 1.1 min) of total S-metabolites. In conclusion, stereoselectivity was suggested both at the hepatic elimination of the parent compound and at the biliary excretion of the metabolites.