Effect of phenobarbital and SKF 525-A on the teratogenicity of cyclophosphamide in mice.

Abstract

AbstractMaternal nontoxic dosages of cyclophosphamide are teratogenic in Swiss‐Webster mice. Phenobarbital induces and SKF 525‐A inhibits liver drug‐metabolizing enzymes in mice. The purpose of this study was to evaluate the effect of SKF 525‐A and phenobarbital on the teratogenicity and development of alkylating activity after cyclophosphamide. Mice were pretreated intraperitoneally with SKF 525‐A (32 mg/kg) or phenobarbital (50 or 100 mg/kg) on days 8, 9, and 10 of gestation. Cyclophosphamide (20 mg/kg, ip) was administered to all groups on day 10. Phenobarbital and SKF 525‐A were not teratogenic. Cyclophosphamide significantly (P < 0.05) reduced the weight of fetuses examined on day 18 of gestation (control, 1.52 vs 0.89 g). SKF 525‐A pretreatment on days 8, 9, and 10 significantly reduced fetal weight from cyclophosphamide (0.79 vs 0.89 g). Phenobarbital pretreatment significantly reversed cyclophosphamide weight effect (1.23 vs. 0.89 g). SKF 525‐A significantly increased the incidence of resorptions, open eyes, polydactyly, aphakia, hydronephrosis, absence or nonossification of ribs, bone fusion. and bone curvature. Phenobarbital abolished cyclophosphamide‐induced limb defects, hydrocephalus, exencephaly, cleft palate, aphakia, and hydronephrosis. Phenobarbital did not affect cyclophosphamide‐induced polydactyly or open eyes. Phenobarbital pretreatment increased and SKF 525‐A pretreatment decreased the concentration of nitrobenzyl pyridine alkylating product of cyclophosphamide (100 mg/kg) in plasma. The teratogenicity of cyclophosphamide may be separate from its alkylating activity.