Developmental pharmacology and toxicology of anti-HIV therapeutic agents: dideoxynucleosides

As the incidence of human immunodeficiency virus (HIV) infection has increased in women over the past decade, the need for safe, effective therapy during pregnancy has increased concomitantly. Although dideoxynucleosides such as 3'-deoxy-3'-azidothymidine (AZT), 2',3'-dideoxyinosine (ddI), 2',3'-dideoxycytidine (ddC), and 2',3'-didehydro-3'-deoxythymidine have been approved for use in the general population, the administration, efficacy, and toxicity of these compounds during pregnancy and development are now being investigated. Initial human studies suggest that maternal use of AZT during pregnancy is well tolerated by both mother and child and provides a promising degree of protection from vertical HIV transmission to the infant. In vitro and animal models have greatly increased our understanding of the distribution and toxicity resulting from fetal dideoxynucleoside exposure. AZT, ddI, and ddC rapidly cross the placenta by simple diffusion but with different rates of transfer. In vivo data confirm the differential transfer of these compounds with AZT fetal exposure approximately twice that of ddI or ddC. Active phosphorylated metabolites have been detected in placental tissue after in vitro perfusion with AZT. The active triphosphate has not been detected in placental perfusion studies or in the fetal rhesus monkey 3 h after maternal exposure to ddI or ddC. Although in vitro and in vivo laboratory animal studies suggest the potential for toxicity with preimplantation exposure, the risk for teratogenic events after postimplantational exposure appears to be low at therapeutically effective concentrations of these dideoxynucleosides.