Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Jun;49(3):325-336.
doi: 10.1007/s10928-022-09806-y. Epub 2022 Jan 28.

Physiologically-based pharmacokinetic model for 2,4-dinitrophenol

Lyndsey F Meyer  1 , Pooja M Rajadhyaksha  1 , Dhaval K Shah  2
Affiliations

Physiologically-based pharmacokinetic model for 2,4-dinitrophenol

Lyndsey F Meyer et al. J Pharmacokinet Pharmacodyn. 2022 Jun.

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.

Keywords: 2,4-Dinitrophenol; Obesity; PBPK.

PubMed Disclaimer

References

    1. Khan SS, Ning H, Wilkins JT, Allen N, Carnethon M, Berry JD, Sweis RN, Lloyd-Jones DM (2018) Association of body mass index with lifetime risk of cardiovascular disease and compression of morbidity. JAMA Cardiol 3(4):280–287. https://doi.org/10.1001/jamacardio.2018.0022 - DOI - PubMed - PMC
    1. Anderson JW, Konz EC, Frederich RC, Wood CL (2001) Long-term weight-loss maintenance: a meta-analysis of US studies. Am J Clin Nutr 74(5):579–584. https://doi.org/10.1093/ajcn/74.5.579 - DOI - PubMed
    1. Araujo JR, Martel F (2012) Sibutramine effects on central mechanisms regulating energy homeostasis. Curr Neuropharmacol 10(1):49–52. https://doi.org/10.2174/157015912799362788 - DOI - PubMed - PMC
    1. Cutting WC, Mehrtens HG, Tainter ML (1933) Actions and uses of dinitrophenol: promising metabolic applications. J Am Med Assoc 101(3):193–195. https://doi.org/10.1001/jama.1933.02740280013006 - DOI
    1. Tainter ML (1934) Low oxygen tensions and temperatures on the actions and toxicity of dinitrophenol. J Pharmacol Exp Ther 51(1):45–58

Publication types

LinkOut - more resources