Effects of phenobarbital or SKF 525A pretreatment on diphenylhydantoin disposition in pregnant mice

Abstract

Teratogenicity of diphenylhydantoin (DPH) in Swiss-Webster mice and alteration of such teratogenicity by pretreatment of mice with phenobarbital or SKF 525A have been demonstrated. The present work reports the effects of phenobarbital (60 mg/kg/day for 3 days) or SKF 525A (40 mg/kg, twice on day prior and once 1 hr before DPH) on DPH metabolism, distribution, and excretion in pregnant Swiss-Webster mice and concentrations in fetuses. Neither pretreatment affected uptake of DPH-4- 14C, 100 mg/kg, 20 μCi/kg, from ip injection sites. Phenobarbital pretreatment enhanced, while SKF 525A decreased, DPH metabolism, excretion, and plasma disappearance. Phenobarbital increased DPH hepatic uptake during the absorption period but subsequently decreased the hepatic storage; SKF 525A increased hepatic storage of DPH. In general, phenobarbital decreased, while SKF 525A increased, DPH concentrations in maternal fat, brain, and muscle. SKF 525A increased, and phenobarbital decreased, DPH concentrations in placenta. In the fetus, phenobarbital pretreatment resulted in lower concentrations and faster removal of DPH; SKF 525A effected high concentrations and more prolonged removal. The DPH found in the fetus after phenobarbital was mainly unbound, unmetabolized DPH (77%), but unbound, metabolized DPH (4%) was significantly greater than control (2%). SKF 525A pretreatment did not significantly alter the portion of total, metabolized, or unmetabolized DPH in the fetus.