Long-Lasting Inhibition of the Transporter-Mediated Hepatic Uptake of Sulfobromophthalein by Cyclosporin A in Rats

Abstract

Cyclosporin A (CsA) is a well known inhibitor of the organic anion-transporting polypeptide (OATP/Oatp) family transporters, causing a large number of transporter-mediated drug-drug interactions in clinical situations. In the present study, we examined the inhibitory effect of CsA on the hepatic uptake of sulfobromophthalein (BSP) in rats, focusing on a long-lasting inhibition. Twenty-one hours after the subcutaneous administration of CsA, the hepatic clearance of BSP was decreased. The liver uptake index study revealed that hepatic uptake of BSP was reduced in CsA-treated rats for at least 3 days. Comparison of uptake studies using isolated hepatocytes prepared from control and CsA-treated rats showed that hepatic uptake in CsA-treated rats was decreased. In primary cultured hepatocytes, after preincubation with CsA, the uptake of [(3)H]BSP was reduced even after removal of CsA from the incubation buffer although a preincubation time dependence was not observed. However, the expression of Oatp1a1 and Oatp1b2, which are involved in the hepatic uptake of BSP, and the amount of intrahepatic glutathione, a driving force of Oatp1a1, did not change in CsA-treated rats. Thus, we can conclude that CsA modulates the transporter function sustainably. It can cause a potent in vivo drug-drug interaction. The modulation of transporters is not caused by reduced expression or driving force of transporters. It may be affected by CsA accumulated in the liver or its metabolites. The inhibitory effect of CsA on the transporter-mediated uptake of BSP cannot be explained by a simple competitive mechanism and a novel mechanism should be considered.