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Impact of Physiological Determinants: Flow, Binding, Transporters and Enzymes on Organ and Total Body Clearances

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Enzyme- and Transporter-Based Drug-Drug Interactions

Abstract

Physiologically based pharmacokinetic (PBPK) models of the intestine, liver, and kidney were developed to examine the influence of transporters as well as enzymes on the area under the curve and clearances of drugs and metabolites. Whole body PBPK models were then developed, with the kidney and intestine or the kidney and liver as the organs for excretion and metabolism. From these PBPK models, the influence of flow, binding, transporters, and enzymes and the presence of competing pathways and competing organs on the areas of the drug and metabolite and total body clearance were defined. These relationships on the drug and metabolite AUC data are extremely useful for understanding the DDI mechanism, transport or metabolism, or both.

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Acknowledgments

The work is supported by the Canadian Institute for Health Research, CIHR (MOP89850).

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Authors and Affiliations

  1. Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada

    K. Sandy Pang & Edwin C.Y. Chow

  2. NoAb BioDiscoveries Inc., Mississauga, ON, Canada

    Huadong Sun

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  1. K. Sandy Pang
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  2. Huadong Sun
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Correspondence to K. Sandy Pang .

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Editors and Affiliations

  1. Leslie Dan Fac. Pharmacy, University of Toronto, College Street 144, Toronto, M5S 3M2, Canada

    K. Sandy Pang

  2. Bristol-Myers Squibb Company, Princeton, 08543, U.S.A.

    A. David Rodrigues

  3. AstraZeneca UK, Alderley Park, Macclesfield, Cheshire, SK10 4TF, United Kingdom

    Raimund M. Peter

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Pang, K.S., Sun, H., Chow, E.C. (2010). Impact of Physiological Determinants: Flow, Binding, Transporters and Enzymes on Organ and Total Body Clearances. In: Pang , K., Rodrigues, A., Peter, R. (eds) Enzyme- and Transporter-Based Drug-Drug Interactions. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-0840-7_5

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