Assessing Drug Interaction and Pharmacokinetics of Loxoprofen in Mice Treated with CYP3A Modulators

Abstract

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

Drug–Drug Interactions Involving Dexamethasone in Clinical Practice: Myth or Reality?

“…However, when 20 mg/kg of indinavir was given orally to pre-treated rats, dexamethasone decreased C max 10-fold, increased t max two-fold, decreased indinavir systemic exposure (as measured by the AUC) three-fold and decreased oral bioavailability from 28% to 12%, which is consistent with a strong involvement of indinavir pre-systemic small intestinal first-pass induction in this drug-drug interaction with dexamethasone [71]. The effects of dexamethasone in decreasing the AUC of several molecules have been reported in more recent studies with several new drugs, known CYP3A substrates in mice and/or rats: a 39% decrease in AUC of tyrosine kinase inhibitor erlotinib [72]; an 85% and 91% decrease in AUC of triptolide and (5R)-5-hydroxytriptolide, an active agent of Tripterygium wilfordii, a Chinese plant used in rheumatisms [73]; a 47% decrease in the AUC of loxoprofen, a cyclooxygenase inhibitor, with the formation of an (OH)-loxoprofen metabolite [74]; a 90% decrease in AUC of abiraterone acetate, a prostate cancer hormonotherapy [75]. Interestingly, the same extent of AUC decrease (56%) was reported with widely used antalgic nefopam in a rat population, the metabolism of which is not fully elucidated; however, suggesting the involvement of CYP3A [76].…”