title: Effects of HMG-CoA reductase inhibitors on the pharmacokinetics of losartan and its main metabolite EXP-3174 in rats: possible role of CYP3A4 and P-gp inhibition by HMG-CoA reductase inhibitors.
abstract: The present study was designed to investigate the effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (atorvastatin, pravastatin, simvastatin) on the pharmacokinetics of losartan and its active metabolite EXP-3174 in rats. Pharmacokinetic parameters of losartan and EXP-3174 in rats were determined after oral and intravenous administration of losartan (9 mg/kg) without and with HMG-CoA reductase inhibitors (1 mg/kg). The effect of HMG-CoA reductase inhibitors on P-gp and cytochrome (CYP) 3A4 activity were also evaluated. Atorvastatin, pravastatin and simvastatin inhibited CYP3A4 activities with IC₅₀ values of 48.0, 14.1 and 3.10 μmol/l, respectively. Simvastatin (1-10 μmol/l) enhanced the cellular uptake of rhodamine-123 in a concentration-dependent manner. The area under the plasma concentration-time curve (AUC₀₋∞) and the peak plasma concentration of losartan were significantly (p < 0.05) increased by 59.6 and 45.8%, respectively, by simvastatin compared to those of control. The total body clearance (CL/F) of losartan after oral administration with simvastatin was significantly decreased (by 34.8%) compared to that of controls. Consequently, the absolute bioavailability (F) of losartan after oral administration with simvastatin was significantly increased by 59.4% compared to that of control. The metabolite-parent AUC ratio was significantly decreased by 25.7%, suggesting that metabolism of losartan was inhibited by simvastatin. In conclusion, the enhanced bioavailability of losartan might be mainly due to inhibition of P-gp in the small intestine and CYP3A subfamily-mediated metabolism of losartan in the small intestine and/or liver and to reduction of the CL/F of losartan by simvastatin.
authors.affiliation: College of Medicine, Dankuk University, Cheonan, South Korea.
authors.forename: Si-Hyung
authors.initials: SH
authors.lastname: Yang
authors.forename: Jun-Shik
authors.initials: JS
authors.lastname: Choi
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Choi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000214:Acyl Coenzyme A / Q000037:antagonists & inhibitors; D000284:Administration, Oral; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D000924:Anticholesteremic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D045744:Cell Line, Tumor; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D007093:Imidazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D007275:Injections, Intravenous; D019808:Losartan / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology; D008148:Lovastatin / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D020112:Rhodamine 123 / Q000378:metabolism; D019821:Simvastatin / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D013777:Tetrazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D013997:Time Factors
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000214:Acyl Coenzyme A; D047228:Angiotensin II Type 1 Receptor Blockers; D000924:Anticholesteremic Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007093:Imidazoles; D013777:Tetrazoles; C008047:3-hydroxy-3-methylglutaryl-coenzyme A; D020112:Rhodamine 123; D008148:Lovastatin; D019821:Simvastatin; D051544:Cytochrome P-450 CYP3A; C066026:losartan carboxylic acid; D019808:Losartan