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Rapid CommunicationAccelerated Communication

PBPK Modeling to Unravel Nonlinear Pharmacokinetics of Verapamil to Estimate the Fractional Clearance for Verapamil N-Demethylation in the Recirculating Rat Liver Preparation

Qi Joy Yang, Luqin Si, Hui Tang, Helle H. Sveigaard, Edwin C. Y. Chow and K. Sandy Pang
Drug Metabolism and Disposition April 2015, 43 (4) 631-645; DOI: https://doi.org/10.1124/dmd.114.062265
Qi Joy Yang
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada (Q.J.Y., L.S., H.T., H.H.S., E.C.Y.C., K.S.P.); School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China (L.S.); School of Pharmacy, Shihezi University, Shihezi, Xinjiang, P.R. China (H.T.); and Denmark Pharmaceutical University, Copenhagen, Denmark (H.H.S.)
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Luqin Si
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada (Q.J.Y., L.S., H.T., H.H.S., E.C.Y.C., K.S.P.); School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China (L.S.); School of Pharmacy, Shihezi University, Shihezi, Xinjiang, P.R. China (H.T.); and Denmark Pharmaceutical University, Copenhagen, Denmark (H.H.S.)
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Hui Tang
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada (Q.J.Y., L.S., H.T., H.H.S., E.C.Y.C., K.S.P.); School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China (L.S.); School of Pharmacy, Shihezi University, Shihezi, Xinjiang, P.R. China (H.T.); and Denmark Pharmaceutical University, Copenhagen, Denmark (H.H.S.)
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Helle H. Sveigaard
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada (Q.J.Y., L.S., H.T., H.H.S., E.C.Y.C., K.S.P.); School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China (L.S.); School of Pharmacy, Shihezi University, Shihezi, Xinjiang, P.R. China (H.T.); and Denmark Pharmaceutical University, Copenhagen, Denmark (H.H.S.)
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Edwin C. Y. Chow
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada (Q.J.Y., L.S., H.T., H.H.S., E.C.Y.C., K.S.P.); School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China (L.S.); School of Pharmacy, Shihezi University, Shihezi, Xinjiang, P.R. China (H.T.); and Denmark Pharmaceutical University, Copenhagen, Denmark (H.H.S.)
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K. Sandy Pang
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada (Q.J.Y., L.S., H.T., H.H.S., E.C.Y.C., K.S.P.); School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China (L.S.); School of Pharmacy, Shihezi University, Shihezi, Xinjiang, P.R. China (H.T.); and Denmark Pharmaceutical University, Copenhagen, Denmark (H.H.S.)
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This article has a correction. Please see:

  • Correction to: “PBPK Modeling to Unravel Nonlinear Pharmacokinetics of Verapamil to Estimate the Fractional Clearance for Verapamil N-Demethylation in the Recirculating Rat Liver Preparation” - July 01, 2015

Abstract

We applied physiologically based pharmacokinetic (PBPK) modeling to study the dose-dependent metabolism and excretion of verapamil and its preformed metabolite, norverapamil, to unravel the kinetics of norverapamil formation via N-demethylation. Various initial verapamil (1, 50, and 100 μM) and preformed norverapamil (1.5 and 5 μM) concentrations, perfused at 12 ml/min, were investigated in the perfused rat liver preparation. Perfusate and bile were collected over 90 minutes, and livers were harvested at the end of perfusion for high-performance liquid chromatography analysis. After correction for the adsorption of 10%–25% dose verapamil and norverapamil onto Tygon tubing and binding to albumin and red blood cell, fitting of verapamil and formed and preformed norverapamil data with ADAPT5 revealed nonlinearity for protein binding, N-demethylation ( Embedded Image nmol/min; Embedded Image μM), formation of other metabolites ( Embedded Image nmol/min; Embedded Image μM), as well as biliary excretion ( Embedded Image nmol/min; Embedded Image μM). The hepatic clearance of verapamil ( Embedded Image ) decreased with the dose (8.16–10.2 ml/min), with values remaining high relative to perfusate blood flow rate among the doses. The hepatic clearance of preformed norverapamil (11 ml/min) remained unchanged for the concentrations studied and approximated perfusate blood flow rate, suggesting a high norverapamil extraction ratio. The fractional formation of norverapamil and biliary excretion of verapamil based on fitted constants were 31.1% and 0.64% of Embedded Image , respectively. Enantiomeric disposition and auto-inhibition of verapamil failed to perturb these estimaties according to PBPK modeling, due to the low values of the Michaelis-Menten constant, K m, and inhibition parameter, k I.

Footnotes

    • Received November 20, 2014.
    • Accepted February 3, 2015.
  • ↵ 1 Current affiliation: School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China.

  • ↵ 2 Current affiliation: Pharmacy School, Shihezi University, Shihezi City, Xinjiang, P.R. China.

  • Q.J.Y. and L.S. contributed equally to this work.

  • L.S. and H.T. were supported by the China Scholarship Council (CSC), and K.S.P. is supported by Canadian Institute of Heath Research (CIHR).

  • The work was presented in part, at the 2014 AAPS Annual Meeting; San Diego, CA.

  • dx.doi.org/10.1124/dmd.114.062265.

  • ↵ Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (4)
Drug Metabolism and Disposition
Vol. 43, Issue 4
1 Apr 2015
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Rapid CommunicationAccelerated Communication

Nonlinear Metabolite Kinetics of Verapamil

Qi Joy Yang, Luqin Si, Hui Tang, Helle H. Sveigaard, Edwin C. Y. Chow and K. Sandy Pang
Drug Metabolism and Disposition April 1, 2015, 43 (4) 631-645; DOI: https://doi.org/10.1124/dmd.114.062265

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Rapid CommunicationAccelerated Communication

Nonlinear Metabolite Kinetics of Verapamil

Qi Joy Yang, Luqin Si, Hui Tang, Helle H. Sveigaard, Edwin C. Y. Chow and K. Sandy Pang
Drug Metabolism and Disposition April 1, 2015, 43 (4) 631-645; DOI: https://doi.org/10.1124/dmd.114.062265
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