Effects of myricetin, an antioxidant, on the pharmacokinetics of losartan and its active metabolite, EXP-3174, in rats: possible role of cytochrome P450 3A4, cytochrome P450 2C9 and P-glycoprotein inhibition by myricetin

摘要: Objectives  The effects of myricetin, a natural flavonoid, on the pharmacokinetics losartan and its active metabolite, EXP-3174, were investigated in rats. Losartan myricetin interact with cytochrome P450 (CYP) enzymes P-glycoprotein, increase use health supplements may result being taken concomitantly as combination therapy to treat or prevent cardiovascular diseases. Methods  pharmacokinetic parameters EXP-3174 determined after oral administration (9 mg/kg) rats presence absence (0.4, 2 8 mg/kg). P-glycoprotein well CYP3A4 CYP2C9 activity also evaluated. Key findings  Myricetin inhibited enzyme 50% inhibition concentration 7.8 13.5 µm, respectively. In addition, significantly enhanced cellular accumulation rhodamine 123 MCF-7/ADR cells overexpressing concentration-dependent manner. altered by compared control. (2 8 mg/kg) increased area under plasma concentration–time curve 31.4–61.1% peak 31.8–50.2%. Consequently, absolute bioavailability (P < 0.05, 2 mg/kg; P < 0.01, There was no significant change time reach concentration, apparent volume distribution at steady state terminal half-life myricetin. Furthermore, concurrent (8 mg/kg) decreased metabolite–parent ratio 20%, implying that inhibit CYP-mediated metabolism EXP-3174. Conclusions  be mainly due CYP3A4- CYP2C9-mediated small intestine liver, efflux pump