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Predicting when Biliary Excretion of Parent Drug is a Major Route of Elimination in Humans

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Abstract

Biliary excretion is an important route of elimination for many drugs, yet measuring the extent of biliary elimination is difficult, invasive, and variable. Biliary elimination has been quantified for few drugs with a limited number of subjects, who are often diseased patients. An accurate prediction of which drugs or new molecular entities are significantly eliminated in the bile may predict potential drug-drug interactions, pharmacokinetics, and toxicities. The Biopharmaceutics Drug Disposition Classification System (BDDCS) characterizes significant routes of drug elimination, identifies potential transporter effects, and is useful in understanding drug-drug interactions. Class 1 and 2 drugs are primarily eliminated in humans via metabolism and will not exhibit significant biliary excretion of parent compound. In contrast, class 3 and 4 drugs are primarily excreted unchanged in the urine or bile. Here, we characterize the significant elimination route of 105 orally administered class 3 and 4 drugs. We introduce and validate a novel model, predicting significant biliary elimination using a simple classification scheme. The model is accurate for 83% of 30 drugs collected after model development. The model corroborates the observation that biliarily eliminated drugs have high molecular weights, while demonstrating the necessity of considering route of administration and extent of metabolism when predicting biliary excretion. Interestingly, a predictor of potential metabolism significantly improves predictions of major elimination routes of poorly metabolized drugs. This model successfully predicts the major elimination route for poorly permeable/poorly metabolized drugs and may be applied prior to human dosing.

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Acknowledgments

We would like to thank Dr. Julian Blagg at the Institute of Cancer Research for critical review of the manuscript, Dr. Gabriele Cruciani and Molecular Discovery Ltd. for generously supplying the VolSurf+ license, and Dr. Michael Bolger and Simulations Plus for generously supplying the ADMET Predictor™ license. Chelsea Hosey was supported in part by NIH Training Grant T32 GM007175.

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Authors and Affiliations

  1. Department of Bioengineering and Therapeutic Sciences, University of California, 533 Parnassus Ave., Room U-68, San Francisco, California, 94143-0912, USA

    Chelsea M. Hosey & Leslie Z. Benet

  2. Department of Chemistry, University of Perugia, Perugia, Italy

    Fabio Broccatelli

  3. Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK

    Fabio Broccatelli

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  1. Chelsea M. Hosey
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  2. Fabio Broccatelli
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Correspondence to Leslie Z. Benet.

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Hosey, C.M., Broccatelli, F. & Benet, L.Z. Predicting when Biliary Excretion of Parent Drug is a Major Route of Elimination in Humans. AAPS J 16, 1085–1096 (2014). https://doi.org/10.1208/s12248-014-9636-1

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