Toxicokinetics and toxicological studies of sodium 9-[2-(phosphonomethoxy) ethyl] adenine in beagle dogs / 中国药理学与毒理学杂志

ABSTRACT

AIM To provide toxicokinetics data for toxicity studies of repeated doses of sodium 9-[2-(phosphonomethoxy) ethyl] adenine (PMEA-Na). METHODS The concentrations of PMEA-Na in plasma and urine were determined by HPLC/MS/MS method after single and multiple iv administrations in dogs. Data were executed by the statistical moment method to acquire the toxicokinetics parameters. Serum biochemical tests and histopathological examination were performed. RESULTS The system exposure of PMEA-Na in dogs was dose-dependent over the dose range of 1.0-6.0 mg·kg-1. The areas under the plasma concentration-time curve of PMEA-Na after single and multiple iv administrations at 1.0, 3.0 and 6.0 mg·kg-1 dosage were (2.3±0.5), (8.4±1.6), (17.5±3.7) and (5.0±0.4), (15.9±3.2), (30.3±4.7)mg·L-1·h, respectively. The urinary excretion of PMEA-Na in 72 h after iv administration was (87.0±4.8)% at the dose of 3.0 mg·kg-1. In 6.0 mg·kg-1 dose group, liver enzyme activity of glutamic-pyruvic transaminase and serum levels of total bilirubin, blood urea nitrogen, creatinine and triglycerides were all significantly elevated; glucose level significantly decreased comparing with the control group. Histopathological observation showed distinct pathological changes in liver and kidney tissues of 6.0 mg·kg-1 dose group. CONCLUSION There was evidence of toxicity after repeated-dose (14 d) of PMEA-Na in dogs and the major toxicity target organs were the kidney and liver.