Developmental toxicity and pharmacokinetics of oral and intravenous phenytoin in the rat

Jeffrey R. Rowland, Pamela E. Binkerd, Andrew G Hendrickx

Research output: Contribution to journalArticle

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)191-202
Number of pages12
JournalReproductive Toxicology
Volume4
Issue number3
DOIs
StatePublished - 1990

Keywords

  • developmental toxicity
  • intravenous
  • oral
  • pharmacokinetics
  • Phenytoin
  • plasma
  • rat
  • Sprague-Dawley

ASJC Scopus subject areas

  • Toxicology

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