title: Effects of licochalcon A on the pharmacokinetics of losartan and its active metabolite, EXP-3174, in rats.
abstract: Losartan and licochalcon A interact with cytochrome P-450 (CYP) enzymes and P-glycoprotein (P-gp), and the increase in the use of health supplements may result in licochalcon A being taken concomitantly with losartan to treat or prevent cardiovascular diseases as a combination therapy. The effect of licochalcon A, a natural flavonoid, on the pharmacokinetics of losartan and its active metabolite, EXP-3174, was investigated in rats. 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 licochalcon A (0.5, 2.5 and 10 mg/kg). The effect of licochalcon A on P-glycoprotein (P-gp) as well as CYP3A4 and 2C9 activities was also evaluated. Licochalcon A inhibited CYP3A4 and CYP2C9 enzyme activities with 50% inhibition concentrations (IC50) of 2.0 and 0.1 microM, respectively. In addition, licochalcon A significantly enhanced the cellular accumulation of rhodamine-123 in a concentration-dependent manner in MCF-7/ADR cells overexpressing P-gp. The pharmacokinetic parameters of losartan were significantly altered by licochalcon A. Licochalcon A (2.5 mg/kg or 10 mg/kg) increased AUC0-infinity of losartan by 33.4-63.2% and Cmax of losartan by 34.0-62.8%. The total body clearance (CL/F) was significantly decreased (2.5 mg/kg, p < 0.05; 10 mg/kg, p < 0.01) by licochalcon A. Consequently, the absolute bioavailability of losartan in the presence of licochalcon A increased significantly (2.5 mg/kg, p < 0.05; 10 mg/kg, p < 0.01) compared to that in the control group. The relative bioavailability (R.B.) of losartan was 1.15- to 1.63-fold greater than that of the control group. However, there was no significant change in Tmax and t1/2 of losartan in the presence of licochalcon A. Licochalcon A (10 mg/kg) increased the AUC0-infinity of EXP-3174 but this was not significant. Furthermore, concurrent use of licochalcon A (10 mg/kg) significantly decreased the metabolite-parent AUC ratio (M.R.) by 20%, suggesting that licochalcon A inhibited the CYP-mediated metabolism of losartan to its active metabolite, EXP-3174. In conclusion, the enhanced oral bioavailability of losartan in the presence of licochalcon A may mainly result from decreased P-gp-mediated efflux transporter in the small intestine and from the inhibition of CYP 3A- and CYP2C9-mediated metabolism in the small intestine and liver and/or from the reduction of total body clearance of losartan by licochalcon A.
authors.affiliation: Department of Food and Drug, Chosun University, Gwangju, Republic of Korea.
authors.forename: J S
authors.initials: JS
authors.lastname: Choi
authors.affiliation: College of Pharmacy, Chosun University, Gwangju, Republic of Korea.
authors.forename: J S
authors.initials: JS
authors.lastname: Choi
authors.affiliation: College of Medicine, Chosun University, Gwangju, Republic of Korea.
authors.forename: D H
authors.initials: DH
authors.lastname: Choi
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000493:pharmacokinetics*; D000818:Animals; D019540:Area Under Curve; D047188:Chalcones / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D019587:Dietary Supplements; D004347:Drug Interactions; D005456:Fluorescent Dyes; D006207:Half-Life; D007093:Imidazoles / Q000378:metabolism*; D019808:Losartan / Q000493:pharmacokinetics*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D020112:Rhodamine 123; D013777:Tetrazoles / Q000378:metabolism*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D047188:Chalcones; D065607:Cytochrome P-450 Enzyme Inhibitors; D005456:Fluorescent Dyes; D007093:Imidazoles; D013777:Tetrazoles; D020112:Rhodamine 123; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A; C066026:losartan carboxylic acid; D019808:Losartan; C070840:licochalcone A