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Research ArticleArticle

Prediction of Human Clearance of Twenty-Nine Drugs from Hepatic Microsomal Intrinsic Clearance Data: An Examination of In Vitro Half-Life Approach and Nonspecific Binding to Microsomes

R. Scott Obach
Drug Metabolism and Disposition November 1999, 27 (11) 1350-1359;
R. Scott Obach
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Abstract

Twenty-nine drugs of disparate structures and physicochemical properties were used in an examination of the capability of human liver microsomal lability data (“in vitroT1/2” approach) to be useful in the prediction of human clearance. Additionally, the potential importance of nonspecific binding to microsomes in the in vitro incubation milieu for the accurate prediction of human clearance was investigated. The compounds examined demonstrated a wide range of microsomal metabolic labilities with scaled intrinsic clearance values ranging from less than 0.5 ml/min/kg to 189 ml/min/kg. Microsomal binding was determined at microsomal protein concentrations used in the lability incubations. For the 29 compounds studied, unbound fractions in microsomes ranged from 0.11 to 1.0. Generally, basic compounds demonstrated the greatest extent of binding and neutral and acidic compounds the least extent of binding. In the projection of human clearance values, basic and neutral compounds were well predicted when all binding considerations (blood and microsome) were disregarded, however, including both binding considerations also yielded reasonable predictions. Including only blood binding yielded very poor projections of human clearance for these two types of compounds. However, for acidic compounds, disregarding all binding considerations yielded poor predictions of human clearance. It was generally most difficult to accurately predict clearance for this class of compounds; however the accuracy was best when all binding considerations were included. Overall, inclusion of both blood and microsome binding values gave the best agreement between in vivo clearance values and clearance values projected from in vitro intrinsic clearance data.

Footnotes

  • Send reprint requests to: R. Scott Obach, Ph.D., Drug Metabolism Department, Candidate Synthesis, Enhancement, and Evaluation, Central Research Division, Pfizer, Inc., Groton, CT 06340. E-mail: obachr{at}pfizer.com

  • Abbreviations used are::
    CL′int
    intrinsic clearance
    fu(mic)
    unbound fraction in microsomal incubation mixtures
    fu(blood)
    unbound fraction in blood
    Q
    hepatic blood flow
    ISTD
    internal standard
    • Received April 9, 1999.
    • Accepted July 30, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (11)
Drug Metabolism and Disposition
Vol. 27, Issue 11
1 Nov 1999
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Research ArticleArticle

Prediction of Human Clearance of Twenty-Nine Drugs from Hepatic Microsomal Intrinsic Clearance Data: An Examination of In Vitro Half-Life Approach and Nonspecific Binding to Microsomes

R. Scott Obach
Drug Metabolism and Disposition November 1, 1999, 27 (11) 1350-1359;

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Research ArticleArticle

Prediction of Human Clearance of Twenty-Nine Drugs from Hepatic Microsomal Intrinsic Clearance Data: An Examination of In Vitro Half-Life Approach and Nonspecific Binding to Microsomes

R. Scott Obach
Drug Metabolism and Disposition November 1, 1999, 27 (11) 1350-1359;
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