Effects of clofibric acid on the biliary excretion of benoxaprofen glucuronide and taurine conjugate in rats.
Benoxaprofen (BOP) is a 2-methyl propionic acid derivative with anti-inflammatory activity. BOP has an asymmetric carbon, and receives chiral inversion from R to S in vivo. BOP is metabolized to glucuronide (BOP-G) and taurine conjugate (BOP-T). The configuration of BOP-G is mainly S, and that of BOP-T is R. Chiral inversion of R to S of the propionic acid moiety and amino acid conjugation of carboxyl compounds proceed via an acyl CoA intermediate. It is known that fibrates, used in hyperlipidemia, induce acyl CoA synthetase and increase CoA concentration. We administered racemic BOP (10 mg/kg body weight) to rats (CFA+) pre-administered clofibric acid (CFA, 280 mg/kg/day), and studied BOP, BOP-G, and BOP-T enantiomer concentrations in plasma and bile up to 12 h after administration. The findings were compared with those in rats (CFA-) that had not received CFA. Furthermore, we studied the amounts of BOP-G enantiomer produced by glucuronidation in vitro using microsomes pretreated with CFA. The amounts of (S)-BOP-G in CFA+ rats were 2.7-fold larger than that in CFA- rats. Although (R)-BOP-T was excreted in CFA- rats, BOP-T could not be detected in CFA+ rats. Plasma clearance values of racemic BOP and (S)-BOP in CFA+ rats were 5-fold and 6-fold larger than those in CFA- rats, respectively. (S)-BOP-G formation activities were higher than (R)-BOP-G formation activities in both CFA+and CFA- microsomes. These findings suggest that CFA increases biliary excretion of (S)-BOP-G and facilitates plasma elimination of BOP, and further suggests that CFA predominantly induces chiral inversion to S rather than metabolic reaction to (R)-BOP-T, resulting in an increase of (S)-BOP-G.
Clinical Pharmaceutics Laboratory, Department of Pharmacy and Health Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Meiji Pharmaceutical University, Tokyo, Japan.
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Okada
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Kanoh
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Mohri
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics* / Q000652:urine; D001646:Bile / Q000378:metabolism*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D002995:Clofibric Acid / Q000494:pharmacology*; D005965:Glucuronates / Q000493:pharmacokinetics* / Q000652:urine; D020719:Glucuronides / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007275:Injections, Intravenous; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011092:Polyethylene Glycols; D011422:Propionates / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D013050:Spectrometry, Fluorescence; D013237:Stereoisomerism; D013654:Taurine / Q000493:pharmacokinetics* / Q000652:urine
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005965:Glucuronates; D020719:Glucuronides; D000960:Hypolipidemic Agents; D007202:Indicators and Reagents; D011422:Propionates; D013654:Taurine; D011092:Polyethylene Glycols; D002995:Clofibric Acid; C055871:benoxaprofen glucuronide