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Drug Metabolism & Disposition

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Hepatocellular Binding of Drugs: Correction for Unbound Fraction in Hepatocyte Incubations Using Microsomal Binding or Drug Lipophilicity Data

Peter J. Kilford, Michael Gertz, J. Brian Houston and Aleksandra Galetin
Drug Metabolism and Disposition July 2008, 36 (7) 1194-1197; DOI: https://doi.org/10.1124/dmd.108.020834
Peter J. Kilford
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Michael Gertz
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J. Brian Houston
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Aleksandra Galetin
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Abstract

Analogous to the fraction unbound in microsomes (fumic), fraction unbound in hepatocyte incubations (fuhep) is an important parameter in the prediction of intrinsic clearance and potential drug-drug interactions. A recent study by Austin et al. (Drug Metab Dispos 33:419–425, 2005) proposed a linear 1:1 relationship between the extent of binding to microsomes at 1 mg/ml and to hepatocytes at 106 million cells/ml. The current study collates a fumic and fuhep database for 39 drugs to examine the relationship between binding in microsomes and hepatocytes. A new nonlinear empirical equation is proposed as an alternative to the linear relationship to relate binding between the two systems. The nonlinear equation results in higher prediction accuracy and lower bias in comparison to the linear relationship, in particular for drugs with fuhep < 0.4. The proposed equation is further extended to allow direct prediction of fuhep from drug lipophilicity data by substituting the fumic term by the Hallifax and Houston predictive equation (Drug Metab Dispos 34:724–726, 2006). The prediction accuracy of this approach is high for relatively hydrophilic drugs (logP/D ≤ 2.5), whereas less accurate prediction of the fuhep is observed for lipophilic drugs (logP > 3), consistent with the limitations observed for microsomal binding predictive tools. In conclusion, the proposed nonlinear equations provide an accurate predictive tool to estimate fuhep for the in vitro-in vivo extrapolation of intrinsic clearance and inhibition parameters.

Footnotes

  • The work was funded by a consortium of pharmaceutical companies (GlaxoSmithKline, Lilly, Novartis, Pfizer, and Servier) within the Centre for Applied Pharmacokinetic Research at the University of Manchester. M.G. and P.J.K. are recipients of Ph.D. studentships from Pfizer and Biotechnology and Biological Sciences Research Council/Novartis, respectively.

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

  • doi:10.1124/dmd.108.020834.

  • ABBREVIATIONS: fumic, fraction unbound in microsomes; fuhep, fraction unbound in hepatocyte incubations; Ka, microsomal protein binding affinity; Kp, hepatocyte/medium concentration ratio; VR, ratio of the cell and incubation volume; logP/D, descriptor for lipophilicity (logP for drugs where pKa > 7.4; logD for drugs where pKa < 7.4); P, microsomal protein concentration.

    • Received February 8, 2008.
    • Accepted April 9, 2008.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 36 (7)
Drug Metabolism and Disposition
Vol. 36, Issue 7
1 Jul 2008
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OtherShort Communication

Hepatocellular Binding of Drugs: Correction for Unbound Fraction in Hepatocyte Incubations Using Microsomal Binding or Drug Lipophilicity Data

Peter J. Kilford, Michael Gertz, J. Brian Houston and Aleksandra Galetin
Drug Metabolism and Disposition July 1, 2008, 36 (7) 1194-1197; DOI: https://doi.org/10.1124/dmd.108.020834

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OtherShort Communication

Hepatocellular Binding of Drugs: Correction for Unbound Fraction in Hepatocyte Incubations Using Microsomal Binding or Drug Lipophilicity Data

Peter J. Kilford, Michael Gertz, J. Brian Houston and Aleksandra Galetin
Drug Metabolism and Disposition July 1, 2008, 36 (7) 1194-1197; DOI: https://doi.org/10.1124/dmd.108.020834
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