Stereoselective pharmacokinetics of [14C]-labeled KE-298, a new anti-rheumatic drug, in rats

The stereoselective pharmacokinetics of two enantiomers of [14C]-labeled KE-298 [2-acetylthiomethyl-4-(4-methylphenyl)-4-oxobutanonic acid] were investigated in rats. The blood levels of radioactivity after the oral administration of (+)-(S)-[14C]KE-298 were higher than that for (-)-(R)-[14C]KE-298; the AUC of the former was approximately twice that of the latter. No significant stereoselectivity was observed in absorption rate. The tissue/ plasma level ratios at 30 min after oral administration of (-)-(R)-[14C]KE-298 in the liver and kidney, the major metabolic and/or excretory organs, were 2 to 3 times higher than those for (+)-(S)-[14C]KE-298. Neither was evidence of stereoselectivity found in the excretion of radioactivity. During incubation with isolated rat hepatocytes in vitro, the metabolic rates of KE-298 enantiomers were not significantly different. Plasma protein binding 20 min after the oral administration of (+)-(S)-[14C]KE-298 and (-)-(R)-[14C]KE-298 was 99.3% and 97.0% respectively. Comparing the unbound fraction, (-)-(R)-[14C]KE-298 was approximately 4 times higher than (+)-(S)-[14C]KE-298. In order to make clear the relationship between stereoselective pharmacokinetics and protein binding for [14C]KE-298, the comparative pharmacokinetics of (+)-(S)-[14C]KE-298 and (-)-(R)-[14C]KE-298 were investigated in analbuminemic rats. In these animals, no evidence of stereoselectivity was found for either blood level-time profiles or plasma protein binding. These results revealed that the stereoselective pharmacokinetics of KE-298 in rats might be due to enantiomeric differences in binding to plasma albumin.