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.
Copyright © 2011 S. Karger AG, Basel.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / analysis
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
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ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
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Acyl Coenzyme A / antagonists & inhibitors
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Administration, Oral
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Angiotensin II Type 1 Receptor Blockers / administration & dosage
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Angiotensin II Type 1 Receptor Blockers / metabolism
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Angiotensin II Type 1 Receptor Blockers / pharmacokinetics*
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Angiotensin II Type 1 Receptor Blockers / pharmacology
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Animals
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Anticholesteremic Agents / blood
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Anticholesteremic Agents / pharmacokinetics*
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Anticholesteremic Agents / pharmacology
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Cell Line, Tumor
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Cytochrome P-450 CYP3A / metabolism*
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Cytochrome P-450 CYP3A Inhibitors
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Disease Models, Animal
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Dose-Response Relationship, Drug
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Drug Interactions
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Female
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Humans
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / blood
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / metabolism
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Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
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Imidazoles / blood
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Imidazoles / pharmacokinetics*
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Imidazoles / pharmacology
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Injections, Intravenous
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Losartan / administration & dosage
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Losartan / metabolism
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Losartan / pharmacokinetics*
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Losartan / pharmacology
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Lovastatin / analogs & derivatives
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Lovastatin / pharmacokinetics
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Lovastatin / pharmacology
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Male
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Rats
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Rats, Sprague-Dawley
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Rhodamine 123 / metabolism
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Simvastatin / blood
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Simvastatin / metabolism
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Simvastatin / pharmacology
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Tetrazoles / blood
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Tetrazoles / pharmacokinetics*
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Tetrazoles / pharmacology
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Time Factors
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Acyl Coenzyme A
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Angiotensin II Type 1 Receptor Blockers
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Anticholesteremic Agents
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Cytochrome P-450 CYP3A Inhibitors
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Hydroxymethylglutaryl-CoA Reductase Inhibitors
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Imidazoles
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Tetrazoles
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3-hydroxy-3-methylglutaryl-coenzyme A
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Rhodamine 123
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Lovastatin
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Simvastatin
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Cytochrome P-450 CYP3A
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losartan carboxylic acid
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Losartan