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Drug Metabolism & Disposition

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Research ArticleArticle

HEPATIC MICROSOME STUDIES ARE INSUFFICIENT TO CHARACTERIZE IN VIVO HEPATIC METABOLIC CLEARANCE AND METABOLIC DRUG-DRUG INTERACTIONS: STUDIES OF DIGOXIN METABOLISM IN PRIMARY RAT HEPATOCYTES VERSUS MICROSOMES

Justine L. Lam and Leslie Z. Benet
Drug Metabolism and Disposition November 2004, 32 (11) 1311-1316; DOI: https://doi.org/10.1124/dmd.32.11.1311
Justine L. Lam
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Leslie Z. Benet
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Abstract

The effects of hepatic uptake and efflux transporters on metabolism of digoxin were examined in isolated rat hepatocytes versus microsomes. The metabolic clearance estimated from microsomes was 4.59 ± 0.69 ml/min/kg. However, the metabolic clearance estimated from hepatocytes was 15.9 ± 3.0 ml/min/kg. The former did not correlate with in vivo clearance (12.9 ml/min/kg) for digoxin. Rifampin (an organic anion-transporting peptide 2 inhibitor) or 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 carboxamide)] (a potent P-glycoprotein inhibitor) were used to estimate effects of uptake or efflux transporters on digoxin metabolism. Whereas both inhibitors exerted minimal effects on metabolism in microsomes, rifampin and GG918 significantly decreased and increased digoxin metabolism in hepatocytes, respectively. Concentration-time course studies further demonstrated that, compared with the area under the curve (AUC) of control (15.6 ± 0.1 μM · min), an increase of AUC (20.1 ± 0.5 μM · min, p < 0.005) was observed when digoxin was coincubated with rifampin and a decrease of AUC (14.1 ± 0.1 μM · min, p < 0.01) when GG918 was also present. Digoxin primary metabolite concentrations changed directionally in an inverse manner with parent drug concentrations, as would be expected. These results strongly suggest that the hepatic uptake and efflux transporters that are found in hepatocytes, but not in microsomes, modulate intracellular concentration of digoxin and thus affect metabolism. We conclude that the interplay of transporters and enzymes must be considered in defining the intrinsic metabolic clearance of the liver and in evaluating potential drug-drug interactions.

Footnotes

  • This study was supported in part by National Institutes of Health Grants HD40543 and GM61390 and in part through facilities of the University of California, San Francisco Liver Center (DK 26743).

  • ABBREVIATIONS: P450, cytochrome P450;P-gp, P-glycoprotein; Slc, solute carrier; Oatp, organic anion-transporting polypeptide; Oat, organic anion transporter; Oct, organic cation transporter; 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 carboxamide); BSA, bovine serum albumin; LC/MS, liquid chromatograph/mass spectrometry; AUC, area under the curve; dg2, digoxigenin bis-digitoxoside; dg1, digoxigenin mono-digitoxoside; dg0, aglycone digoxigenin; IPRL, isolated perfused rat liver.

    • Received December 1, 2003.
    • Accepted August 17, 2004.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 32 (11)
Drug Metabolism and Disposition
Vol. 32, Issue 11
1 Nov 2004
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Research ArticleArticle

HEPATIC MICROSOME STUDIES ARE INSUFFICIENT TO CHARACTERIZE IN VIVO HEPATIC METABOLIC CLEARANCE AND METABOLIC DRUG-DRUG INTERACTIONS: STUDIES OF DIGOXIN METABOLISM IN PRIMARY RAT HEPATOCYTES VERSUS MICROSOMES

Justine L. Lam and Leslie Z. Benet
Drug Metabolism and Disposition November 1, 2004, 32 (11) 1311-1316; DOI: https://doi.org/10.1124/dmd.32.11.1311

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Research ArticleArticle

HEPATIC MICROSOME STUDIES ARE INSUFFICIENT TO CHARACTERIZE IN VIVO HEPATIC METABOLIC CLEARANCE AND METABOLIC DRUG-DRUG INTERACTIONS: STUDIES OF DIGOXIN METABOLISM IN PRIMARY RAT HEPATOCYTES VERSUS MICROSOMES

Justine L. Lam and Leslie Z. Benet
Drug Metabolism and Disposition November 1, 2004, 32 (11) 1311-1316; DOI: https://doi.org/10.1124/dmd.32.11.1311
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