Developmental toxicity and pharmacokinetics of oral and intravenous phenytoin in the rat.
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.
Rowland
J R
JR
California Primate Research Center, University of California, Davis 95616.
Binkerd
P E
PE
Hendrickx
A G
AG
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
D010672:Phenytoin