Stereoselective disposition and chiral inversion of KE-298, a new antirheumatic drug, in rats.
The present study was an attempt to elucidate the relationship between stereoselective pharmacokinetics and protein binding of KE-298 and its active metabolites, deacetyl-KE-298 (M-1) and S-methyl-KE-298 (M-2). Metabolic chiral inversion was also investigated. The levels of unchanged KE-298 in plasma after oral administration of (+)-(S)-KE-298 to rats were lower than those of (-)-(R)-KE-298, whereas the levels of M-1 and M-2 after administration of (+)-(S)-KE-298 were higher than after (-)-(R)-KE-298. In vitro, rat plasma protein binding of (+)-(S)-KE-298 was lower than that of (-)-(R)-KE-298. In contrast, the binding of (+)-(S)-M-1 and (+)-(S)-M-2 was higher than that of (-)-(R)-M-1 and (-)-(R)-M-2. Displacement studies revealed that the (+)-(S) and (-)-(R)- enantiomers of KE-298 and their metabolites bound to the warfarin binding site on rat serum albumin. These results suggested that the stereoselective plasma levels in KE-298 and its metabolites were closely related to enantiomeric differences in protein binding attributed to quantitative differences in binding to albumin rather than to the different binding sites. Unidirectional chiral inversion was detected after oral administration of either (-)-(R)-KE-298 or (-)-(R)-M-2 to rats both yielding (+)-(S)-M-2.
Yoshida
H
H
Department of Drug Metabolism, Taisho Pharmaceutical Co., Ltd., Saitama, Japan.
Kohno
Y
Y
Endo
H
H
Ohmi
N
N
Fukushima
K
K
Suwa
T
T
Hayashi
M
M
D000818:Animals; D018501:Antirheumatic Agents / Q000378:metabolism / Q000493:pharmacokinetics*; D001798:Blood Proteins / Q000378:metabolism; D008297:Male; D010666:Phenylpropionates / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism
D018501:Antirheumatic Agents; D001798:Blood Proteins; D010666:Phenylpropionates; C078547:esonarimod