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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Multiple Transporters Affect the Disposition of Atorvastatin and Its Two Active Hydroxy Metabolites: Application of in Vitro and ex Situ Systems

Yvonne Y. Lau, Hideaki Okochi, Yong Huang and Leslie Z. Benet
Journal of Pharmacology and Experimental Therapeutics February 2006, 316 (2) 762-771; DOI: https://doi.org/10.1124/jpet.105.093088
Yvonne Y. Lau
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Hideaki Okochi
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Yong Huang
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Leslie Z. Benet
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Abstract

Atorvastatin (ATV) is primarily metabolized by CYP3A in the liver to form two active hydroxy metabolites. Therefore, the sequential transport system governed by hepatic uptake and efflux transporters is important for the drug disposition and metabolism. Here, we assessed the interaction of ATV with hepatic uptake transporter organic anion transporting polypeptide (Oatp) and efflux transporter multidrug resistance associated protein 2 (MRP2/Mrp2) in vitro and ex situ using the isolated perfused rat liver (IPRL). Rifampicin (RIF) was chosen as an inhibitor for Oatp in both uptake and IPRL studies. Its inhibitory effects on MRP2 and metabolism were also tested using MRP2-overexpressing cells and rat microsomes, respectively. Our results indicate that RIF effectively inhibits the Oatp-mediated uptake of ATV and its metabolites. Inhibition on MRP2-mediated efflux of ATV was also observed at a high RIF concentration. Compared with ATV alone in the IPRL, the area under the curve(s) (AUC) of ATV was significantly increased by RIF, whereas the AUC of both metabolites were also increased in a concentration-dependent manner. However, the extent of metabolism was significantly reduced, as reflected by the reduced amounts of metabolites detected in RIF-treated livers. In conclusion, inhibition of Oatp-mediated uptake seems to be the major determinant for interaction between ATV and RIF. Metabolites of ATV were subject to Oatp-mediated uptake as well, suggesting that they undergo a similar disposition pathway as the parent drug. These data emphasize the relevance of uptake transporter as being one of the major players in hepatic drug elimination, even for substrates that undergo metabolism.

Footnotes

  • This study was supported in part by National Institutes of Health Grant GM-61390 and an unrestricted grant from Amgen, Inc. Dr. Benet serves as a consultant to Amgen.

  • A portion of this data was presented at the American Association of Pharmaceutical Scientists (AAPS) Annual Meeting, Baltimore, MD; 2004, November 7-11, and Gordon Research Conference on Drug Metabolism, Plymouth, NH; 2005, July 10-15.

  • Y.Y.L. was supported in part by an American Foundation for Pharmaceutical Education Predoctoral Fellowship.

  • doi:10.1124/jpet.105.093088.

  • ABBREVIATIONS: ATV, atorvastatin; MDCK, Madin-Darby canine kidney; MDR1, multidrug resistance gene; P-gp, P-glycoprotein; cMOAT, canalicular multiorganic anion transporter; MII, MDCKII; M-MDR1, MDCK-MDR1; MRP2/Mrp2, multidrug resistance-associated protein 2; HEK293, human embryonic kidney 293; OATP/Oatp, organic anion-transporting polypeptide; A, apical; B, basolateral; LC, liquid chromatography; MS, mass spectrometry; FBS, fetal bovine serum; IPRL, isolated perfused rat liver; PBS, phosphate-buffered saline; P450, cytochrome P450; AUC, area under the curve(s); 2-OH ATV, ortho-hydroxy atorvastatin; 4-OH ATV, para-hydroxy atorvastatin; HPLC, high-performance liquid chromatography; RIF, rifampicin; GG918 (GF120918), N-{4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)-ethyl]-phenyl}-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamine.

    • Received July 23, 2005.
    • Accepted October 27, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 316 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 316, Issue 2
1 Feb 2006
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Multiple Transporters Affect the Disposition of Atorvastatin and Its Two Active Hydroxy Metabolites: Application of in Vitro and ex Situ Systems

Yvonne Y. Lau, Hideaki Okochi, Yong Huang and Leslie Z. Benet
Journal of Pharmacology and Experimental Therapeutics February 1, 2006, 316 (2) 762-771; DOI: https://doi.org/10.1124/jpet.105.093088

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Multiple Transporters Affect the Disposition of Atorvastatin and Its Two Active Hydroxy Metabolites: Application of in Vitro and ex Situ Systems

Yvonne Y. Lau, Hideaki Okochi, Yong Huang and Leslie Z. Benet
Journal of Pharmacology and Experimental Therapeutics February 1, 2006, 316 (2) 762-771; DOI: https://doi.org/10.1124/jpet.105.093088
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