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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Ex Situ Inhibition of Hepatic Uptake and Efflux Significantly Changes Metabolism: Hepatic Enzyme-Transporter Interplay

Yvonne Y. Lau, Chi-Yuan Wu, Hideaki Okochi and Leslie Z. Benet
Journal of Pharmacology and Experimental Therapeutics March 2004, 308 (3) 1040-1045; DOI: https://doi.org/10.1124/jpet.103.061770
Yvonne Y. Lau
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Chi-Yuan Wu
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Hideaki Okochi
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Leslie Z. Benet
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Abstract

The disposition of digoxin and the influence of the organic anion transporting polypeptide (Oatp)2 inhibitor rifampicin and the P-glycoprotein (P-gp) inhibitor quinidine on its hepatic disposition were examined in the isolated perfused rat liver. Livers from groups of rats were perfused in a recirculatory manner after a bolus dose of digoxin (10 μg), a dual substrate for Oatp2 and P-gp as well as CYP3A. Perfusions of digoxin were also examined in groups of rats in the presence of the inhibitors: rifampicin (100 μM) or quinidine (10 μM). In all experiments, perfusate samples were collected for 60 min. Digoxin and its primary metabolite were determined in perfusate and liver by liquid chromatography/mass spectrometry. The area under the curve (AUC) from 0 to 60 min was determined. The AUC ± S.D. of digoxin was increased from control (3880 ± 210 nM·min) by rifampicin (5200 ± 240 nM·min; p < 0.01) and decreased by quinidine (3220 ± 340 nM·min; P < 0.05). It is concluded that rifampicin limits the hepatic entrance of digoxin and reduced the hepatic exposure of digoxin to CYP3A by inhibiting the basolateral Oatp2 uptake transport, whereas quinidine increased the hepatic exposure of digoxin to CYP3A by inhibiting the canalicular P-gp transport. These data emphasize the importance of uptake and efflux transporters on hepatic drug metabolism.

Footnotes

  • This study was supported in part by National Institutes of Health Grant GM-61390 and an unrestricted grant from Amgen, Inc.

  • DOI: 10.1124/jpet.103.061770.

  • ABBREVIATIONS: SLC, solute carrier superfamily; OATP, organic anion transporting polypeptide; OAT, organic anion transporter; P-gp, P-glycoprotein; IPRL, isolated perfused rat liver; Dg2, digoxigenin bisdigitoxoside; HPLC, high-performance liquid chromatography; AUC, area under the curve; MDR1, multidrug resistance gene; GG918, 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 October 17, 2003.
    • Accepted November 17, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 308 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 308, Issue 3
1 Mar 2004
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Ex Situ Inhibition of Hepatic Uptake and Efflux Significantly Changes Metabolism: Hepatic Enzyme-Transporter Interplay

Yvonne Y. Lau, Chi-Yuan Wu, Hideaki Okochi and Leslie Z. Benet
Journal of Pharmacology and Experimental Therapeutics March 1, 2004, 308 (3) 1040-1045; DOI: https://doi.org/10.1124/jpet.103.061770

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Ex Situ Inhibition of Hepatic Uptake and Efflux Significantly Changes Metabolism: Hepatic Enzyme-Transporter Interplay

Yvonne Y. Lau, Chi-Yuan Wu, Hideaki Okochi and Leslie Z. Benet
Journal of Pharmacology and Experimental Therapeutics March 1, 2004, 308 (3) 1040-1045; DOI: https://doi.org/10.1124/jpet.103.061770
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