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Hepatic Nuclear Factor 1α Inhibitor Ursodeoxycholic Acid Influences Pharmacokinetics of the Organic Anion Transporting Polypeptide 1B1 Substrate Rosuvastatin and Bilirubin

Yi-Jing He, Wei Zhang, Jiang-Hua Tu, Julia Kirchheiner, Yao Chen, Dong Guo, Qing Li, Zhong-Yu Li, Hao Chen, Dong-Li Hu, Dan Wang and Hong-Hao Zhou
Drug Metabolism and Disposition August 2008, 36 (8) 1453-1456; DOI: https://doi.org/10.1124/dmd.108.020503
Yi-Jing He
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Wei Zhang
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Jiang-Hua Tu
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Julia Kirchheiner
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Yao Chen
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Dong Guo
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Qing Li
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Zhong-Yu Li
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Hao Chen
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Dong-Li Hu
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Dan Wang
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Hong-Hao Zhou
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Abstract

Expression of the organic anion transporting polypeptide 1B1 (OATP1B1) is regulated by transcription factor hepatic nuclear factor (HNF) 1α. The aim of this study was to investigate the effect of ursodeoxycholic acid (UDCA), an inhibitor of transcription factor HNF1α, on rosuvastatin and bilirubin kinetics in human healthy volunteers. Both substances are substrates of OATP1B1. Twelve subjects with OATP1B1*1b/*1b genotype predicting high transport activity were recruited for this randomized, crossover study. Each subject received a single p.o. dose of 20 mg of rosuvastatin after 14 days of p.o. intake of either 500 mg of UDCA or placebo. Plasma concentrations of rosuvastatin were determined on days 15 to 18 of each study period. Subjects were randomly assigned to UDCA or placebo group. Intake of UDCA led to a significant increase in rosuvastatin area under the curve (AUC)0–72 from 128.5 ng/ml · h to 182.1 ng/ml · h(P = 0.008) compared with the control group. The oral clearance decreased from 155.2 l/h with placebo to 109.8 l/h with UDCA. In addition, the mean values of total bilirubin, conjugated bilirubin, and unconjugated bilirubin significantly increased to 139 ± 39% (P = 0.003), 127 ± 29% (P = 0.005), and 151 ± 52% (P = 0.004), respectively, after UDCA treatment. These results in healthy volunteers confirm the findings from in vitro studies that UDCA inhibits OATP1B1 activity by inhibition of the transcription factor HNF1α. They highlight a novel mechanism of OATP1B1-based interaction that is mediated by transcription factor HNF1α.

Footnotes

  • This work was supported by the National Natural Scientific Foundation of China Grants F30130210, C30000211, and C30200346 and by China Medical Board of New York Grants 99-697 and 01-755. Rosuvastatin was provided by Jae-Gook Shin, Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Busan, Korea.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.108.020503.

  • ABBREVIATIONS: OATP, organic anion transporting polypeptide; AUC, area under the curve; HNF1α, hepatic nuclear factor 1α; UDCA, ursodeoxycholic acid; TB, total bilirubin; CB, conjugated bilirubin; UB, unconjugated bilirubin; NTCP, sodium-dependent taurocholate cotransporting polypeptide.

    • Received January 16, 2008.
    • Accepted April 23, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (8)
Drug Metabolism and Disposition
Vol. 36, Issue 8
1 Aug 2008
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OtherShort Communication

Hepatic Nuclear Factor 1α Inhibitor Ursodeoxycholic Acid Influences Pharmacokinetics of the Organic Anion Transporting Polypeptide 1B1 Substrate Rosuvastatin and Bilirubin

Yi-Jing He, Wei Zhang, Jiang-Hua Tu, Julia Kirchheiner, Yao Chen, Dong Guo, Qing Li, Zhong-Yu Li, Hao Chen, Dong-Li Hu, Dan Wang and Hong-Hao Zhou
Drug Metabolism and Disposition August 1, 2008, 36 (8) 1453-1456; DOI: https://doi.org/10.1124/dmd.108.020503

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OtherShort Communication

Hepatic Nuclear Factor 1α Inhibitor Ursodeoxycholic Acid Influences Pharmacokinetics of the Organic Anion Transporting Polypeptide 1B1 Substrate Rosuvastatin and Bilirubin

Yi-Jing He, Wei Zhang, Jiang-Hua Tu, Julia Kirchheiner, Yao Chen, Dong Guo, Qing Li, Zhong-Yu Li, Hao Chen, Dong-Li Hu, Dan Wang and Hong-Hao Zhou
Drug Metabolism and Disposition August 1, 2008, 36 (8) 1453-1456; DOI: https://doi.org/10.1124/dmd.108.020503
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