title: Developmental toxicity and pharmacokinetics of oral and intravenous phenytoin in the rat.
abstract: Correlations between oral and intravenous (i.v.) doses of phenytoin, maternal plasma levels, and subsequent developmental toxicity were examined in the Sprague-Dawley rat. Oral administration of 150 to 1500 mg/kg and i.v. administration of 25 to 100 mg/kg phenytoin from gestational days (GD) 8 to 17 resulted in a dose-dependent increase in maternal death and toxicity [impaired motor function, decreased maternal weight gain (oral dose only)], embryolethality, and intrauterine growth retardation, in addition to significant increases in craniofacial (1125 mg/kg oral; 75 mg/kg i.v.) and urogenital (1125 mg/kg oral) malformations. Pharmacokinetic sampling in oral and i.v. groups on GD 8-9 and 16-17 revealed significant increases in maternal drug exposure over the treatment period, as evidenced by 2- to 3-fold increases in total plasma phenytoin (bound + free) half-life, area under the concentration curve, peak concentration (oral dose only), and decreases in clearance. These findings emphasize the importance of pharmacokinetics in the evaluation of phenytoin-induced developmental toxicity.
authors: California Primate Research Center, University of California, Davis 95616.
authors: J R
authors: JR
authors: Rowland
authors: P E
authors: PE
authors: Binkerd
authors: A G
authors: AG
authors: Hendrickx
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000473:pathology; D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D005260:Female; D005327:Fetal Resorption / Q000139:chemically induced; D006207:Half-Life; D007275:Injections, Intravenous; D009929:Organ Size / Q000187:drug effects; D010672:Phenytoin / Q000493:pharmacokinetics / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains; D012098:Reproduction / Q000187:drug effects
chemical_list: D010672:Phenytoin