Effects of Cyclosporine A and Itraconazole on Permeability, Biliary Excretion and Pharmacokinetics of Amlidipine

Liang      Ni; Xue      Yu; Qiaoling      Yu; Xijing      Chen; Lee      Jia

doi:10.2174/187231208785425782

Abstract

Cyclosporin A (CsA) is a P-glycoprotein (P-gp) inhibitor clinically used as an immunosuppressant. Itraconazole (ITZ) functions as an inhibitor of both the P-gp and CYP3A and is used as afungistatic/fungicidal agent in human and veterinary medicine. The present studies were designed to investigate the effects of CsA and ITZ on 1 intestinal permeability of amlodipine (a calcium channel blocker used as a cardiovascular agent) in isolated rat everted gut sac modle, and 2) biliary excretion and pharmacokinetics of amlodipine in rats. The concentrations of amlodipine in biosamples were measured by the liquid chromatograph mass spectrometer (LC/MS). Both CsA ITZ significantly increased permeability of amlodipine in the ileum and jejunum of the rat everted gut sac modle,and ITZ showed more potent than CsA IN this modle. Pretreatment pf rats with ITZ increased plasma levels and biliary excretion of amlodipine and made no changes in its plasma levels. In conclusion, ITZ inreased in vitro permeability of amlod ipine and bile in vivo. Whereas, CsA showed no significant efects on the levels of amlodipine in rat plasma and bile in vivo. Whereas, CsA showed no significant effects on the levels of amlodipine in rat plasma and bile probably due to the potent inhibition of ITZ against both CYP3A and P-gp.

Keywords: Amlodipine, cyclosporin A, itraconazole, P-glycoprotein, CYP3A, permeability, biliary exretion, pharmacokinerics