Phenytoin disposition in the pregnant rat. Dose-dependent studies and salicylate effects

Studies were conducted in 19-day gestation Sprague-Dawley rats to investigate the dose dependency and effects of salicylate coadministration on phenytoin disposition during pregnancy. After iv loading doses of both drugs, concurrent iv infusions of 75.6, 151.2, or 302.4 micrograms/min/kg of 14C-phenytoin and 65, 130, or 195 micrograms/min/kg of salicylate were administered for 180 min. Maternal plasma, fetal plasma, and whole fetus samples were obtained during the infusions, and maternal tissue (heart, skeletal muscle, fat, liver, and brain) and cerebrospinal fluid specimens were collected at the termination of drug administration. All samples were assayed for phenytoin and p-hydroxydiphenylhydantoin by liquid scintillation counting following separation by TLC. Systemic and intrinsic phenytoin clearance, which averaged 12 and 41.5 ml/min/kg, respectively, for the three phenytoin infusions, were both dose independent, and were unaltered by the three salicylate treatments. Similarly, the maternal tissue-to-plasma concentration ratios for phenytoin and p-hydroxydiphenylhydantoin were dose and/or concentration independent following the three phenytoin infusions, and were also not affected by salicylate coadministration. Additionally, the fetal distribution ratios for whole fetus-to-maternal plasma and whole fetus-to-fetal plasma were also invariant for the three phenytoin infusions and salicylate treatments. The results showed that the maternal and fetal disposition of phenytoin was dose and concentration independent and unaltered by salicylate coadministration with the dosages studied.