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 30 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)-[^14CC]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. © 1996 Wiley-Liss, Inc.