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Research ArticleMetabolism, Transport, and Pharmacogenomics

Mechanistic PBPK Modeling of Urine pH Effect on Renal and Systemic Disposition of Methamphetamine and Amphetamine

Weize Huang, Lindsay C. Czuba and Nina Isoherranen
Journal of Pharmacology and Experimental Therapeutics June 2020, 373 (3) 488-501; DOI: https://doi.org/10.1124/jpet.120.264994
Weize Huang
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington
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Lindsay C. Czuba
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington
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Nina Isoherranen
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington
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Abstract

The effect of urine pH on renal excretion and systemic disposition has been observed for many drugs and metabolites. When urine pH is altered, tubular ionization, passive reabsorption, renal clearance, and systemic exposure of drugs and metabolites may all change dramatically, raising clinically significant concerns. Surprisingly, the urine pH effect on drug disposition is not routinely explored in humans, and regulatory agencies have neither developed guidance on this issue nor required industry to conduct pertinent human trials. In this study, we hypothesized that physiologically based pharmacokinetic (PBPK) modeling could be used as a cost-effective method to examine potential urine pH effect on drug and metabolite disposition. Our previously developed and verified mechanistic kidney model was integrated with a full-body PBPK model to simulate renal clearance and area under the plasma concentration-time curve (AUC) with varying urine pH statuses using methamphetamine and amphetamine as model compounds. We first developed and verified drug models for methamphetamine and amphetamine under normal urine pH condition [absolute average fold error (AAFE) < 1.25 at study level]. Then, acidic and alkaline urine scenarios were simulated. Our simulation results show that the renal excretion and plasma concentration-time profiles for methamphetamine and amphetamine could be recapitulated under different urine pH (AAFE < 2 at individual level). The methamphetamine-amphetamine parent-metabolite full-body PBPK model also successfully simulated amphetamine plasma concentration-time profiles (AAFE < 1.25 at study level) and amphetamine/methamphetamine urinary concentration ratios (AAFE < 2 at individual level) after dosing methamphetamine. This demonstrates that our mechanistic PBPK model can predict urine pH effect on systemic and urinary disposition of drugs and metabolites.

SIGNIFICANCE STATEMENT Our study shows that integrating mechanistic kidney model with full-body physiologically based pharmacokinetic model can predict the magnitude of alteration in renal excretion and area under the plasma concentration-time curve (AUC) of drugs and metabolites when urine pH is changed. This provides a cost-effective method to evaluate the likelihood of renal and systemic disposition changes due to varying urine pH. This is important because multiple drugs and diseases can alter urine pH, leading to quantitatively and clinically significant changes in drug and metabolite disposition that may require adjustment of therapy.

Footnotes

    • Received January 5, 2020.
    • Accepted March 18, 2020.
  • This work was supported by National Institutes of Health Grant P01 DA032507. W.H. was supported by Warren G. Magnuson Scholarship and William E. Bradley Fellowship from the University of Washington, Seattle, WA.

  • https://doi.org/10.1124/jpet.120.264994.

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

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 373 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 373, Issue 3
1 Jun 2020
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Research ArticleMetabolism, Transport, and Pharmacogenomics

PBPK Modeling of Urine pH Effect

Weize Huang, Lindsay C. Czuba and Nina Isoherranen
Journal of Pharmacology and Experimental Therapeutics June 1, 2020, 373 (3) 488-501; DOI: https://doi.org/10.1124/jpet.120.264994

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Research ArticleMetabolism, Transport, and Pharmacogenomics

PBPK Modeling of Urine pH Effect

Weize Huang, Lindsay C. Czuba and Nina Isoherranen
Journal of Pharmacology and Experimental Therapeutics June 1, 2020, 373 (3) 488-501; DOI: https://doi.org/10.1124/jpet.120.264994
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