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Physiologically-based pharmacokinetic model for 2,4-dinitrophenol

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Abstract

New approaches in drug development are needed to address the growing epidemic of obesity as the prevalence of obesity increases worldwide. 2,4-Dinitrophenol (DNP) is an oxidative phosphorylation uncoupling agent that was widely used in the early 1930s for weight loss but was quickly banned by the FDA due to the severe toxicities associated with the compound. One of the limitations leading to the demise of DNP as a pharmaceutical was a lack of understanding about the pharmacokinetic–pharmacodynamic relationship. The purpose of this study was to investigate whole body disposition of DNP in order to understand the relationship between the pharmacokinetics, efficacy and toxicity in the C57BL/6J diet induced obese mouse model. Following intravenous administration of 1 mg/kg, and intraperitoneal administration of 5 mg/kg and 15 mg/kg of DNP, we found limited DNP distribution to tissues. Experimentally measured partition coefficients were found to be less than 1 for all analyzed tissues. In addition, DNP exhibits significant nonlinear pharmacokinetics, which we have attributed to nonlinear plasma protein binding and nonlinear partitioning into liver and kidney. By enhancing our understanding of the PK–PD relationship, we can develop new approaches to leverage oxidative phosphorylation uncoupling as a weight loss strategy.

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Abbreviations

DNP:

2,4-Dinitrophenol

PK:

Pharmacokinetics

PD:

Pharmacodynamics

PBPK:

Physiologically based, pharmacokinetics

TD:

Toxicodynamics

DIO:

Diet induced obese

IV:

Intravenous

IP:

Intraperitoneal

LC–MS/MS:

Liquid chromatography–mass spectrometry

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Acknowledgements

This work was supported by NIH Grant GM114179 and AI138195 to D.K.S. and the Centre for Protein Therapeutics at University at Buffalo. L.F.M would like to acknowledge Donald F. and Edna G. Bishop Scholarship Foundation for their continued support.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York at Buffalo, 455 Pharmacy Building, Buffalo, NY, 14214-8033, USA

    Lyndsey F. Meyer, Pooja M. Rajadhyaksha & Dhaval K. Shah

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  1. Lyndsey F. Meyer
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  2. Pooja M. Rajadhyaksha
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Correspondence to Dhaval K. Shah.

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Meyer, L.F., Rajadhyaksha, P.M. & Shah, D.K. Physiologically-based pharmacokinetic model for 2,4-dinitrophenol. J Pharmacokinet Pharmacodyn 49, 325–336 (2022). https://doi.org/10.1007/s10928-022-09806-y

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  • DOI: https://doi.org/10.1007/s10928-022-09806-y

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