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 [3H]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.
Footnotes
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This study was supported in part by a Grant-in-Aid for Young Scientists (B) [Grant 17790130] provided by the Ministry of Education, Culture, Sports, Science and Technology of Japan; and the Japan Research Foundation for Clinical Pharmacology.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.025544.
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ABBREVIATIONS: CsA, cyclosporin A; OATP/Oatp, organic anion-transporting polypeptide; AUC, area under the plasma concentration-time curve; P450, cytochrome P450; Mrp, multidrug resistance-associated protein; BSP, sulfobromophthalein; SD, Sprague-Dawley; PE, polyethylene; TBS-T, Tris-buffered saline containing 0.05% Tween 20; BSA, bovine serum albumin; PCR, polymerase chain reaction; RT-PCR, reverse transcription-PCR; KHB, Krebs-Henseleit buffer; LUI, liver uptake index; MBI, mechanism-based inhibition.
- Received November 5, 2008.
- Accepted March 9, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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