Abstract

The purpose of this study was to evaluate the effect of phenobarbital and SKF 525A pretreatment on the placental transfer of cyclophosphamide in mice. Phenobarbital and SKF 525A pretreatments produce a corresponding decrease and increase in cyclophosphamide teratogenicity. ¹⁴C-cyclophosphamide (20 mg/kg i.p., specific activity 026 µc/µmol) was administered on day 10 of gestation. Peak maternal plasma levels of radioactivity of nonpretreated and phenobarbital-pretreated mice were noted at 8 minutes. Peak plasma radioactivity was noted at 16 minutes in SKF 525A-pretreated mice. Plasma radioactivity in all groups was one-tenth the peak activity 256 minutes later. In nonpretreated mice, maternal liver had the highest radioactivity and placenta the lowest at 8 minutes. Radioactivity in embryos was markedly affected by pretreatment: SKF 525A significantly (P < 05) increased embryo radioactivity content over control level at 8 to 128 minutes. Phenobarbital pretreatment significantly reduced embryo radioactivity measured at 32 and 64 minutes. The fraction of unchanged drug present was increased by SKF 525A pretreatment in embryos, amnionic fluid and maternal plasma and urine. Phenobarbital pretreatment decreased the fraction of unchanged drug. The differences in radioactivity in embryos were due to unchanged cyclophosphamide rather than to cyclophosphamide metabolites. Modification of the cyclophosphamide teratogenic responses in mice by phenobarbital and SKF 525A pretreatments appears to be due to alteration in the amount of unchanged cyclophosphamide which reaches the embryo.