Species differences in loxoprofen reductase activities: Roles of aldo-keto and carbonyl reductases in humans and rats.

Abstract

Loxoprofen is a widely used nonsteroidal anti-inflammatory drug designed as a prodrug to reduce gastrointestinal (GI) injury by hepatic biotransformation to its active form, trans-hydroxyloxoprofen. Preclinical studies in rats have suggested a relatively low incidence of GI injury with loxoprofen, whereas GI injury has been reported clinically. Although direct comparison between species is limited by differences in experimental and clinical conditions, species differences in loxoprofen metabolism may contribute to this discrepancy. We therefore compared the hepatic and intestinal metabolism of loxoprofen between humans and rats. In humans, the intrinsic clearance for trans-hydroxyloxoprofen formation was higher in the small intestine (16.3 mL/min per kg) than in the liver (10.5 mL/min per kg), whereas the opposite was observed in rats (2.5 vs 21.1 mL/min per kg, respectively). This human-specific intestinal metabolism was attributed to high expression of aldo-keto reductase (AKR) 1C3 and carbonyl reductase (CBR) 1. Recombinant rat Akr1c1, Akr1c14, and Cbr1 showed catalytic activity toward loxoprofen. Among them, Akr1c1 exhibited the highest activity and was expressed at higher levels in the liver than in the small intestine; however, it mainly produced inactive cis-hydroxyloxoprofen. Akr1c14 activity was insufficient to explain cytosolic activity in rat tissues, and Cbr1 expression was negligible in rat liver. Thus, enzymes other than Akr and Cbr families may be involved in loxoprofen metabolism in rat tissues. Overall, this study revealed a fundamental species difference in the reductive metabolism of loxoprofen, and the higher intestinal metabolic activity in humans may contribute to GI injury risk, although its clinical relevance requires further investigation. SIGNIFICANCE STATEMENT: This study identifies a species difference in the reductive activation of the prodrug loxoprofen, demonstrating that humans exhibit higher intestinal than hepatic metabolic activity, whereas rats show the opposite pattern. The intestinal expression and contribution of AKR1C3 and CBR1 in humans further highlight species differences in loxoprofen metabolism that may influence exposure to the active metabolite. These findings underscore intestinal metabolism and species-specific enzyme expression in translational pharmacokinetics and safety.

Abstract as supplied by the indexing source. © the authors / publisher.