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Research ArticleArticle

Prediction of Human Drug Clearance by Multiple Metabolic Pathways: Integration of Hepatic and Intestinal Microsomal and Cytosolic Data

Helen E. Cubitt, J. Brian Houston and Aleksandra Galetin
Drug Metabolism and Disposition May 2011, 39 (5) 864-873; DOI: https://doi.org/10.1124/dmd.110.036566
Helen E. Cubitt
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J. Brian Houston
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Aleksandra Galetin
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Abstract

The current study assesses hepatic and intestinal glucuronidation, sulfation, and cytochrome P450 (P450) metabolism of raloxifene, quercetin, salbutamol, and troglitazone using different in vitro systems. The fraction metabolized by conjugation and P450 metabolism was estimated in liver and intestine, and the importance of multiple metabolic pathways on accuracy of clearance prediction was assessed. In vitro intrinsic sulfation clearance (CLint, SULT) was determined in human intestinal and hepatic cytosol and compared with hepatic and intestinal microsomal glucuronidation (CLint, UGT) and P450 clearance (CLint, CYP) expressed per gram of tissue. Hepatic and intestinal cytosolic scaling factors of 80.7 mg/g liver and 18 mg/g intestine were estimated from published data. Scaled CLint, SULT ranged between 0.7 and 11.4 ml · min−1 · g−1 liver and 0.1 and 3.3 ml · min−1 · g−1 intestine (salbutamol and quercetin were the extremes). Salbutamol was the only compound with a high extent of sulfation (51 and 28% of total CLint for liver and intestine, respectively) and also significant renal clearance (26–57% of observed plasma clearance). In contrast, the clearance of quercetin was largely accounted for by glucuronidation. Drugs metabolized by multiple pathways (raloxifene and troglitazone) demonstrated improved prediction of intravenous clearance using data from all hepatic pathways (44–86% of observed clearance) compared with predictions based only on the primary pathway (22–36%). The assumption of no intestinal first pass resulted in underprediction of oral clearance for raloxifene, troglitazone, and quercetin (3–22% of observed, respectively). Accounting for the intestinal contribution to oral clearance via estimated intestinal availability improved prediction accuracy for raloxifene and troglitazone (within 2.5-fold of observed). Current findings emphasize the importance of both hepatic and intestinal conjugation for in vitro-in vivo extrapolation of metabolic clearance.

Footnotes

  • The work was supported by a consortium of pharmaceutical companies (GlaxoSmithKline, Lilly, Novartis, Pfizer, and Servier) within the Centre for Applied Pharmacokinetic Research at the University of Manchester.

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

    doi:10.1124/dmd.110.036566.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    UGT
    UDP-glucuronosyltransferase
    SULT
    sulfotransferase
    PAPS
    3′-phosphoadenosine-5′-phosphosulfate
    HLC
    human liver cytosol
    HIC
    human intestinal cytosol
    HLM
    human liver microsome(s)
    LC
    liquid chromatography
    MS/MS
    tandem mass spectrometry.

  • Received September 30, 2010.
  • Accepted February 8, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (5)
Drug Metabolism and Disposition
Vol. 39, Issue 5
1 May 2011
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Research ArticleArticle

Prediction of Human Drug Clearance by Multiple Metabolic Pathways: Integration of Hepatic and Intestinal Microsomal and Cytosolic Data

Helen E. Cubitt, J. Brian Houston and Aleksandra Galetin
Drug Metabolism and Disposition May 1, 2011, 39 (5) 864-873; DOI: https://doi.org/10.1124/dmd.110.036566

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Research ArticleArticle

Prediction of Human Drug Clearance by Multiple Metabolic Pathways: Integration of Hepatic and Intestinal Microsomal and Cytosolic Data

Helen E. Cubitt, J. Brian Houston and Aleksandra Galetin
Drug Metabolism and Disposition May 1, 2011, 39 (5) 864-873; DOI: https://doi.org/10.1124/dmd.110.036566
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