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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

In Vitro Analysis of Human Drug Glucuronidation and Prediction of in Vivo Metabolic Clearance

M. G. Soars, B. Burchell and R. J. Riley
Journal of Pharmacology and Experimental Therapeutics April 2002, 301 (1) 382-390; DOI: https://doi.org/10.1124/jpet.301.1.382
M. G. Soars
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B. Burchell
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R. J. Riley
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Abstract

The glucuronidation of a number of commonly used hepatic uridine diphosphate glucuronosyltransferase drug substrates has been studied in human tissue microsomes. Prediction of in vivo hepatic drug glucuronidation from liver microsomal data yielded a consistent 10-fold underprediction. Consideration of protein binding was observed to be pivotal when predicting in vivo glucuronidation for acid substrates. Studies using human intestinal microsomes demonstrated the majority of drugs to be extensively glucuronidated such that the intrinsic clearance (CLint) of ethinylestradiol (CLint = 1.3 μl/min/mg) was twice that obtained using human liver microsomes (CLint = 0.7 μl/min/mg). The potential extrahepatic in vivo glucuronidation was calculated for a range of drug substrates from human microsomal data. These results indicate the contribution of intestinal drug glucuronidation to systemic drug clearance to be much less than either hepatic or renal glucuronidation. Therefore, data obtained with intestinal microsomes may be misleading in the assessment of the contribution of this organ to systemic glucuronidation. The use of hepatocytes to assess metabolic stability for drugs predominantly metabolized by glucuronidation was also investigated. Metabolic clearances for a range of drugs obtained using fresh preparations of human hepatocytes predicted accurately hepatic clearance reported in vivo. The use of cryopreserved hepatocytes as an in vitro tool to predict in vivo metabolism was also assessed with an excellent correlation obtained for a number of extensively glucuronidated drugs (R2 = 0.80, p < 0.001).

Footnotes

  • This work was funded by AstraZeneca and The Wellcome Trust.

  • Abbreviations:
    CLint
    intrinsic clearance
    P450
    cytochrome P450
    HKM
    human kidney microsomes
    UGT
    uridine diphosphate glucuronosyltransferase
    HLM
    human liver microsomes
    UDPGA
    uridine diphosphate glucuronic acid
    HIM
    human intestine microsomes
    HPLC
    high-performance liquid chromatography
    BSA
    bovine serum albumin
    fu
    unbound fraction in plasma
    fu inc
    unbound fraction in in vitro microsomal incubation
    HH
    human hepatocyte
    • Received September 7, 2001.
    • Accepted December 12, 2001.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 301 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 301, Issue 1
1 Apr 2002
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

In Vitro Analysis of Human Drug Glucuronidation and Prediction of in Vivo Metabolic Clearance

M. G. Soars, B. Burchell and R. J. Riley
Journal of Pharmacology and Experimental Therapeutics April 1, 2002, 301 (1) 382-390; DOI: https://doi.org/10.1124/jpet.301.1.382

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

In Vitro Analysis of Human Drug Glucuronidation and Prediction of in Vivo Metabolic Clearance

M. G. Soars, B. Burchell and R. J. Riley
Journal of Pharmacology and Experimental Therapeutics April 1, 2002, 301 (1) 382-390; DOI: https://doi.org/10.1124/jpet.301.1.382
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