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

J Pharm Pharmacol. 2010 Jul;62(7):908-14. doi: 10.1211/jpp.62.07.0012.

Abstract

Objectives: The effects of myricetin, a natural flavonoid, on the pharmacokinetics of losartan and its active metabolite, EXP-3174, were investigated in rats. Losartan and myricetin interact with cytochrome P450 (CYP) enzymes and P-glycoprotein, and the increase in the use of health supplements may result in myricetin being taken concomitantly with losartan as a combination therapy to treat or prevent cardiovascular diseases.

Methods: The pharmacokinetic parameters of losartan and EXP-3174 were determined after oral administration of losartan (9 mg/kg) to rats in the presence or absence of myricetin (0.4, 2 and 8 mg/kg). The effects of myricetin on P-glycoprotein as well as CYP3A4 and CYP2C9 activity were also evaluated.

Key findings: Myricetin inhibited CYP3A4 and CYP2C9 enzyme activity with a 50% inhibition concentration of 7.8 and 13.5 microm, respectively. In addition, myricetin significantly enhanced the cellular accumulation of rhodamine 123 in MCF-7/ADR cells overexpressing P-glycoprotein in a concentration-dependent manner. The pharmacokinetic parameters of losartan were significantly altered by myricetin compared with the control. The presence of myricetin (2 or 8 mg/kg) increased the area under the plasma concentration-time curve of losartan by 31.4-61.1% and peak plasma concentration of losartan by 31.8-50.2%. Consequently, the absolute bioavailability of losartan in the presence of myricetin increased significantly (P < 0.05, 2 mg/kg; P < 0.01, 8 mg/kg) compared with the control. There was no significant change in the time to reach the peak plasma concentration, apparent volume of distribution at steady state or terminal half-life of losartan in the presence of myricetin. Furthermore, concurrent use of myricetin (8 mg/kg) significantly decreased the metabolite-parent area under the plasma concentration-time curve ratio by 20%, implying that myricetin may inhibit the CYP-mediated metabolism of losartan to its active metabolite, EXP-3174.

Conclusions: The enhanced bioavailability of losartan may be mainly due to inhibition of the CYP3A4- and CYP2C9-mediated metabolism of losartan in the small intestine or in the liver, and the P-glycoprotein efflux pump in the small intestine by myricetin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
  • Animals
  • Antioxidants / pharmacology
  • Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors
  • Biological Availability
  • Cytochrome P-450 CYP2C9
  • Cytochrome P-450 CYP3A Inhibitors
  • Cytochrome P-450 Enzyme Inhibitors*
  • Flavonoids / pharmacology*
  • Herb-Drug Interactions*
  • Imidazoles / metabolism*
  • Losartan / metabolism
  • Losartan / pharmacokinetics*
  • Male
  • Plant Extracts / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Tetrazoles / metabolism*

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antioxidants
  • Cytochrome P-450 CYP3A Inhibitors
  • Cytochrome P-450 Enzyme Inhibitors
  • Flavonoids
  • Imidazoles
  • Plant Extracts
  • Tetrazoles
  • CYP2C9 protein, human
  • Cytochrome P-450 CYP2C9
  • Aryl Hydrocarbon Hydroxylases
  • losartan carboxylic acid
  • Losartan