In vitro and in vivo studies on the prenatal toxicity of five virustatic nucleoside analogues in comparison to aciclovir

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Abstract
Several virustatic agents are known to be teratogenic in laboratory animals. Since routinely performed in vivo studies do not always offer the best conditions to detect the teratogenic potential of a drug, we used a combined in vivo/in vitro approach for comparative studies on the prenatal toxicity of five nucleoside analogues. Rat embryos were exposed for 48 h to various concentrations of vidarabine-phosphate (VAP), ganciclovir (GCV), 2′,3′-dideoxyadenosine (ddA), 2′,3′-dideoxycytidine (ddC) and zidovudine (= azidothymidine, AZT) in a whole-embryo culture system. The steepness of the concentration-response curves as well as the induced abnormality pattern (head, neural tube, shape) were similar for these compounds. However, a wide range in embryotoxic potency was observed: VAP was the most potent compound (100% abnormal embryos at 25 μM) in this in vitro system, while AZT showed the lowest potency to interfere with normal embryonic development (40% abnormal embryos at 3000 μM). In addition to these experiments we treated rats on day 10 of gestation with three s.c. injections (8 a.m.; 12 a.m.; 4 p.m.) of 200 mg of each drug/kg body wt. The embryos were evaluated on day 11.5 of gestation, i.e. at a time of development corresponding to the developmental stage at the end of the whole-embryo culture. The same criteria were used as during the in vitro studies for the evaluation of these in vivo exposed embryos. With VAP and GCV we obtained similar results with both exposure routes (in vitro and in vivo), while no abnormalities were detectable with the other compounds after exposure in utero. When the results from the in vitro and in vivo studies are compared with data of similar experiments conducted in our laboratory with the nucleoside analogue aciclovir (ACV) under identical conditions (Klug et al. 1985 a; Stahlmann et al. 1988), the following conclusions can be drawn: under in vitro conditions VAP showed the highest potential of the virustatics to interfere with embryonic development, the toxic potential of AZT was surprisingly low. Under our experimental in vivo conditions ACV reveals the highest teratogenic potential, whereas ddC, ddA, and AZT exhibited an obviously lower toxicity.