Loxoprofen (LOX) is a non-selective cyclooxygenase inhibitor that is widely used for\nthe treatment of pain and inflammation caused by chronic and transitory conditions. Its alcoholic\nmetabolites are formed by carbonyl reductase (CR) and they consist of trans-LOX, which is active,\nand cis-LOX, which is inactive. In addition, LOX can also be converted into an inactive hydroxylated\nmetabolite (OH-LOXs) by cytochrome P450 (CYP). In a previous study, we reported that CYP3A4 is\nprimarily responsible for the formation of OH-LOX in human liver microsomes. Although metabolism\nby CYP3A4 does not produce active metabolites, it can affect the conversion of LOX into trans-/cis-LOX,\nsince CYP3A4 activity modulates the substrate LOX concentration. Although the pharmacokinetics\n(PK) and metabolism of LOX have been well defined, its CYP-related interactions have not been\nfully characterized. Therefore, we investigated the metabolism of LOX after pretreatment with\ndexamethasone (DEX) and ketoconazole (KTC), which induce and inhibit the activities of CYP3A,\nrespectively. We monitored their effects on the PK parameters of LOX, cis-LOX, and trans-LOX in\nmice, and demonstrated that their PK parameters significantly changed in the presence of DEX or\nKTC pretreatment. Specifically, DEX significantly decreased the concentration of the LOX active\nmetabolite formed by CR, which corresponded to an increased concentration of OH-LOX formed\nby CYP3A4. The opposite result occurred with KTC (a CYP3A inhibitor) pretreatment. Thus, we\nconclude that concomitant use of LOX with CYP3A modulators may lead to drugâ??drug interactions\nand result in minor to severe toxicity even though there is no direct change in the metabolic pathway\nthat forms the LOX active metabolite.
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