Measurement of unbound pravastatin in rat blood and bile on the perspective of hepatobiliary excretion and its interaction with cyclosporin A and berberine

We develop a rapid and sensitive method using a microdialysis coupled with liquid chromatography to determine unbound pravastatin in rat blood and bile for additional pharmacokinetic study. Microdialysis probes were simultaneously inserted into the jugular vein toward heart and bile duct of male Sprague-Dawley rats for sampling in biological fluids following the administration of pravastatin through the femoral vein. The experiments were divided into three groups; in the control group, rats received pravastatin alone (1, 3 or 10 mg kg(-1); i.v.). In the drug-treated groups, 10 min prior to pravastatin administration, rats were given cyclosporin A (CsA; 10 mg kg(-1), i.v.) or berberine (10 mg kg(-1), i.v.). In the drug-pretreated group, berberine was orally administered for three consecutive days. The results indicate that pravastatin went through concentrative excretion into the bile against a concentration gradient based on the very high value of bile-to-blood distribution ratio of about 240. The active pravastatin efflux might be affected by P-gp because co-administration of CsA significantly decreased the pravastatin AUC in the bile in a dose-dependent manner. Conversely, taking berberine by acute concomitance or chronic 3-day pretreatment could increase the pravastatin AUC in the bile, which indicates the possible involvement of P-gp in the biliary excretion of pravastatin. Other transporter systems could not be excluded, but the present results give important evidence that pravastatin probably implicate P-gp transportation. According to the pharmacokinetic study, the drug-drug or herb-drug interactions of pravastatin should be warned with P-gp related drugs. (c) 2005 Elsevier B.V. All rights reserved.