Preclinical Pharmacokinetics and Toxic Kinetics Study of 2, 4-Dinitrophenol (DNP)

Abstract

1.1. Purpose: To research the pharmacokinetics and tissue distribution of 2,4-dinitrophenol (DNP) in tumor-bearing mice and the pharmacokinetics and toxicokinetics in beagle dogs. 1.2. Methods: a. Pharmacokinetics in tumor-bearing mice: DNP was administrated intra tumorally to the mice with three different dosages, the drug concentration and tissue distribution were determined by the HPLC at different time, then analyze the pharmacokinetic parameters. b. Pharmacokinetics in beagle dogs: DNP was intravenously administrated in forelimb with three different dosages and drug concentrations were determined in dog’s plasma before and after each injection to calculate pharmacokinetic parameters. c. Toxicokinetics: the beagle dogs received intramuscular injection for two weeks and the plasma on the first day and the 13th day after the treatment were collected for the toxicity evaluation. 1.3. Results: i. DNP showed the characteristics of linear dynamic when administrated intra temporally in mice from the dosage of 8mg/kg to 32mg/kg. DNP was widely distributed with the relative targets including liver, kidney and lung. ii. Pharmacokinetics in beagle dogs: both of the elimination half time (T1/2) and the area under curve (AUC) of DNP increased with the increasing dose of DNP, showed the characteristics of non-linear dynamics. The systemic toxicity increased with the increasing dose of DNP, showed the characteristics of linear dynamics after multiple injections. No drug accumulation or sex differences happened in beagle dogs. 1.4. Conclusion: DNP is a relatively safe agent, showing the characteristics of linear dynamics after intratumor and intramuscular injection. Thus, the study provides reference for the clinical application.