title: Placental transfer and pharmacokinetics of a single oral dose of [14C]p-nitrophenol in rats.
abstract: The pharmacokinetics and placental transfer of a single oral dose of 100 mg/kg (10 microCi/kg, 16% of acute oral LD50) of uniformly phenyl-labeled [14C]p-nitrophenol were investigated in pregnant Sprague-Dawley rats at 14-18 days of gestation. Three animals were killed on gestation day 18, at 0.5, 1, 2, 4, 12, 24, and 48 h after dosing. Radioactivity was rapidly absorbed and distributed throughout the maternal and fetal tissues. The gastrointestinal tract contents retained 20% and 2% of the dose at 0.5 h and 4 h after dosing. The peak maternal plasma concentration of radioactivity (microg p-nitrophenol equivalent/ml) was 7.17 compared with 0.37 for fetal plasma at 0.5 h. Maximum concentration of radioactivity (microg p-nitrophenol equivalent/g fresh tissue) was detected in most tissues 0.5 h after dosing and was in descending order: kidney 23.27, liver 12.37, placenta 3.56, fetus 2.17, and brain 1.99. Radioactivity was eliminated from plasma and all tissues beiexponentially. The half-lives of elimination of 14C were 34.65 h and 69.30 h for maternal and fetal plasma, respectively. p-Nitrophenol, detected by HPLC, was the major compound identified in plasma and tissues. While p-nitrophenol disappeared biphasically from maternal plasma and kidney, it was eliminated monophasically from brain, placenta, and liver. p-Nitrocatechol and p-aminophenol were detected in the liver with peak concentrations at 0.5 h of 1.13 and 1.00 microg/g fresh tissue, respectively. While the change in the concentration of p-nitrocatechol with time was monophasic, that of p-aminophenol showed a biphasic pattern with elimination half-lives of 1.93 h and 4.95 h, respectively. Radioactivity was rapidly excreted in the urine mostly as polar metabolites, while only 3% of the dose was recovered in the feces. Radioactive materials excreted in the urine comprised: glucuronides 4%, sulfates 8%, hot-acid hydrolysates 11%, nonconjugated compounds 16%, and water-soluble metabolites 61%. This study demonstrated that although orally administered p-nitrophenol is a rapidly absorbed and excreted compound, it is transported to the maternal brain and the fetus and may pose a health risk following exposure to toxic doses during pregnancy.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: A W
authors.initials: AW
authors.lastname: Abu-Qare
authors.forename: C F
authors.initials: CF
authors.lastname: Brownie
authors.forename: M B
authors.initials: MB
authors.lastname: Abou-Donia
mesh_terms: D000818:Animals; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006207:Half-Life; D008431:Maternal-Fetal Exchange / Q000502:physiology*; D009596:Nitrophenols / Q000493:pharmacokinetics*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
chemical_list: D002250:Carbon Radioisotopes; D009596:Nitrophenols; C024836:4-nitrophenol