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Elucidating the Metabolism of 2,4-Dibromophenol in Plants
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Physiologically-based pharmacokinetic model for 2,4-dinitrophenol.

Lyndsey F Meyer1, Pooja M Rajadhyaksha1, Dhaval K Shah2

  • 1Department 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.

Journal of Pharmacokinetics and Pharmacodynamics
|January 28, 2022
PubMed
Summary

2,4-Dinitrophenol (DNP) was investigated for weight loss due to its oxidative phosphorylation uncoupling properties. This study revealed limited tissue distribution and nonlinear pharmacokinetics, crucial for understanding its efficacy and toxicity.

Keywords:
2,4-DinitrophenolObesityPBPK

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Area of Science:

  • Pharmacology
  • Toxicology
  • Metabolic Research

Background:

  • Obesity is a growing global health concern requiring novel drug development strategies.
  • 2,4-Dinitrophenol (DNP), an oxidative phosphorylation uncoupler, was previously used for weight loss but was withdrawn due to toxicity.
  • A poor understanding of its pharmacokinetic-pharmacodynamic (PK-PD) relationship contributed to DNP's withdrawal.

Purpose of the Study:

  • To investigate the whole-body disposition of DNP in diet-induced obese mice.
  • To elucidate the relationship between DNP's pharmacokinetics, efficacy, and toxicity.
  • To inform the development of new weight loss strategies utilizing oxidative phosphorylation uncoupling.

Main Methods:

  • Administration of DNP via intravenous (1 mg/kg) and intraperitoneal (5 mg/kg, 15 mg/kg) routes in C57BL/6J diet-induced obese mice.
  • Measurement of DNP distribution to various tissues.
  • Determination of partition coefficients and analysis of pharmacokinetic parameters.

Main Results:

  • Limited distribution of DNP to tissues was observed, with partition coefficients below 1 for all analyzed tissues.
  • DNP demonstrated significant nonlinear pharmacokinetics.
  • Nonlinear plasma protein binding and nonlinear partitioning into liver and kidney were identified as key factors contributing to nonlinear PK.

Conclusions:

  • Understanding the PK-PD relationship of DNP is essential for its potential therapeutic application.
  • The nonlinear pharmacokinetics and limited tissue distribution of DNP present challenges for its use as a weight loss drug.
  • Further research into oxidative phosphorylation uncouplers could lead to safer and more effective obesity treatments.