Vol. 27, Issue 1, 158-160, January 1999

SHORT COMMUNICATION
In Vivo Studies on Chiral Inversion and Amino Acid Conjugation of 2-[4-(3-Methyl-2-thienyl)phenyl]propionic Acid in Rats and Dogs

Tadao Konishi, Hitoshi Nishikawa, Shigeyuki Kitamura, and Kiyoshi Tatsumi

Research and Development Laboratories,
Maruho Co., Ltd.,
Osaka, Japan (T.K., H.N.);
Institute of Pharmaceutical Sciences,
Hiroshima University
School of Medicine,
Hiroshima, Japan. (S.K., K.T.)

The relationship between chiral inversion and stereoselective amino acid conjugation of a new nonsteroidal anti-inflammatory agent, R,S-2-[4-(3-methyl-2-thienyl)phenyl]propionic acid (R,S-MTPPA) was investigated in rats and dogs. Only the S-enantiomer was found in plasma after oral administration of S-MTPPA to both species. In contrast, the R- and S-enantiomers were both detected after the dosing of R-MTPPA. In rats, the area under the curve of S-MTPPA in plasma was only 9% of that of R-MTPPA when R-MTPPA was dosed, whereas in dogs it was 2.5 times larger than that of the R-enantiomer. After administration of R-MTPPA, both enantiomers appeared in the urine. In rats, a small amount of S-enantiomer was found in the urine, whereas in the case of dogs the amount of the S-enantiomer was larger than that of the R-enantiomer. It appears that R-MTPPA is chirally inverted to S-MTPPA in both rats and dogs, although the extent of chiral inversion is greater in dogs than in rats. In dogs, the taurine conjugate was detected in plasma, urine and feces as a major metabolite after oral administration of either R- or S-MTPPA. In this case, only S-MTPPA-taurine was detected in the urine after the administration of S-MTPPA, and it was also the main component after administration of R-MTPPA.