Enhancement of chlorcyclizine teratogenicity in the rat by coadministration of calcium chelating agents.
Chlorcyclizine and structurally related drugs induce a high incidence of cleft palate and skeletal malformations in fetal rats. We have shown previously that these teratogens bind tightly and reversibly to chondroitin sulfate of cartilage and compete with calcium for binding. Experiments reported here demonstrate that co-administration of calcium chelating agents with chlorcyclizine significantly increases both the frequency of malformations and retention of [14C] chlorcyclizine by embryos. Retention of radioactive teratogen by embryos is inverse to retention of [45Ca]calcium. These findings suggest that drug binding to embryonic glycosaminoglycans is involved in the pathogenesis of malformations produced by chlorcyclizine.
D000014:Abnormalities, Drug-Induced; D000818:Animals; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism*; D002614:Chelating Agents / Q000494:pharmacology; D002972:Cleft Palate / Q000209:etiology; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005865:Gestational Age; D010879:Piperazines / Q000378:metabolism / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D013723:Teratogens
D002614:Chelating Agents; D010879:Piperazines; D013723:Teratogens; D002118:Calcium