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

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,SMTPPA) 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 Rand 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 Ror 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. R,S-2-[4-(3-Methyl-2-thienyl)phenyl]propionic acid (R,S-MTPPA), a 2-arylpropionic acid derivative, is a new, orally effective, nonsteroidal anti-inflammatory agent. The S-isomer is pharmacologically active, whereas the R-isomer is inactive in vitro. The biological activities of S-MTPPA (code: M-5011) in animal models have been reported (Murakami et al., 1996; Kataoka et al., 1997; Tobetto et al., 1997; Kido et al., 1998). In our previous article, the disposition of S-MTPPA was studied after oral administration to rats, dogs, and monkeys using the C-labeled drug. It was confirmed that the drug was metabolized mainly by oxidation of the thiophenyl moiety in these animals and by glucuronidation of the carboxyl group in rats and monkeys. In contrast, a major urinary and fecal metabolite in dogs was identified as the taurine conjugate of R,S-MTPPA (R,S-MTPPATAU) by means of isolation followed by mass spectrometry and H NMR analyses (Konishi et al., 1998a). It is well known that enantiomers of 2-arylpropionic acid derivatives undergo chiral inversion from Rto S-isomer (Yamaguchi and Nakamura, 1987; Caldwell et al., 1988; Baillie et al., 1989; Shirley et al., 1995). This chiral inversion is general, although variations exist among species and drugs (Lee et al., 1985; Mayer et al., 1988; Muller et al., 1990). The Rand S-enantiomers of 2-arylpropionic acid derivatives are known to have different pharmaceutical activities. For example, the inflammatory activities of the S-enantiomers of ibuprofen, naproxen, carprofen, and fenoprofen are stronger than those of the R-enantiomers in vitro (Gaut et al., 1975; Adams et al., 1976; Buttinoni et al., 1983; Kean et al., 1989). Therefore, an understanding of the extent of chiral inversion of the drugs is needed for analysis of pharmaceutical activity and toxicity. The mechanism of chiral inversion of 2-arylpropionic acid derivatives is thought to involve the CoA thioester as an intermediate (Nakamura et al., 1981). The CoA thioester is also a common intermediate of amino acid conjugation of 2-arylpropionic acid derivatives (Hutt and Caldwell, 1990; Asami et al., 1995). In this paper, we report the relationship of chiral inversion and taurine conjugation of MTPPA after administration of Ror S-MTPPA to rats and dogs. Materials and Methods Materials. The enantiomers of R,S-MTPPA and their taurine and glycine conjugates were prepared at the Maruho Kyoto Research Laboratory (Kyoto, Japan) as described in a previous article (Konishi et al., 1998a). Animals and Drug Administration. Sprague-Dawley strain male rats, 7 to 8 weeks old (weighing 170–240 g), were purchased from Japan SLC Inc. (Shizuoka, Japan). Male beagle dogs, 7 to 9 months old (weighing 14.1–14.7 kg), were purchased from Shimidzu Jikkenzairyo Inc. (Kyoto, Japan), and were given pellet food (DS, Oriental Yeast Co. Ltd., Tokyo, Japan). Sor R-MTPPA was suspended in 0.5% carboxymethylcellulose sodium salt solution at the concentration of 10 mg/5 ml/kg for dosing and was orally administered to rats. The dogs received oral administration of Sor R-MTPPA in the dose of 10 mg/kg in a capsule. Determination of Enantiomers of R,S-MTPPA. Extraction of R,SMTPPA from plasma and urine was carried out by solid-liquid extraction and liquid-liquid extraction with diethyl ether. One milliliter of plasma or urine was treated with 2 ml of 0.2 N HCl and applied to a Sep-Pak C18 column (Waters, Milford, CT), which had been pretreated with 10 ml of methanol and 10 ml of water. The column was washed with 3 ml each of water, 1% acetic acid, and Abbreviations used are: MTPPA, 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid; MTPPA-TAU, 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid taurine conjugate; MTPPA-CoA, 2-[4-(3-methyl-2-thienyl)phenyl]propionic acid CoA thioester; HPLC, high-performance liquid chromatography; AUC, area under the curve. Send reprint requests to: Dr. Shigeyuki Kitamura, Institute of Pharmaceutical Sciences, Hiroshima University, School of Medicine, 1-2-3, Kasumi, Minami-ku, Hiroshima 734, Japan. E-mail address: [email protected] 0090-9556/99/2701-0158–160$02.00/0 DRUG METABOLISM AND DISPOSITION Vol. 27, No. 1 Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. 158 at A PE T Jornals on July 7, 2017 dm d.aspurnals.org D ow nladed from