Effects of cyclosporine A and itraconazole on permeability, biliary excretion and pharmacokinetics of amlodipine.

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 a fungistatic/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 model, 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 and ITZ significantly increased permeability of amlodipine in the ileum and jejunum of the rat everted gut sac model, and ITZ showed more potent than CsA in this model. Pretreatment of rats with ITZ increased plasma levels and biliary excretion of amlodipine in a dose-dependent manner. In contrast, pretreatment with CsA slightly decreased biliary excretion of amlodipine and made no changes in its plasma levels. In conclusion, ITZ increased in vitro permeability of amlodipine and its levels in 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.