EXPERIMENTAL ALTERATION OF THE METABOLISM OF CHLORCYCLIZINE AND THE INCIDENCE OF CLEFT PALATE IN RATS

Chlorcyclizine, when administered to pregnant rats from days 10 to 15 or 12 to 15 of gestation, was found in the fetus, placenta and maternal tissues both as unchanged chlorcyclizine and its demethylated derivative, norchlorcyclizine. Other metabolites, if present, were minor. The ratio of norchlorcyclizine to chlorcyclizine was 3:1 to 15:1 from days 13 to 18 of gestation. In urine, the concentration of chlorcyclizine-N-oxide exceeded that of chlorcyclizine or norchlorcyclizine. By means of co-administration of SKF 525A with C 14 -chlorcyclizine, the concentration of chlorcyclizine in the fetus was increased by 6- to 12-fold while the concentration of norchlorcyclizine was decreased to ⅓ to ½ its previous level. Again there was evidence for the presence of only minimal concentrations of other metabolites. The administration of chlorcyclizine or norchlorcyclizine was shown previously to induce a syndrome of birth defects in rats. In the present experiments, the incidence of cleft palate in the fetus due to chlorcyclizine administration could be reduced by co-administration of SKF 525A. The incidence due to norchlorcyclizine administration was not reduced. Possible explanations for the findings are discussed.