Prenatal toxicity of acyclovir in rats

Abstract

Pregnant rats were treated during organogenesis with s.c. injections of acyclovir and the embryos were evaluated on day 11.5 of gestation (crown-rump length, somites, protein content, score, abnormalities, histological examination). After eight injections of 50 mg/kg body wt on days 9, 10, and 11 of pregnancy a reduction of the crown-rump length was noticed. After 100 mg/kg this effect was more pronounced. With two or three applications of this dose on day 10 specific embryonic abnormalities were visible: the shape of the head was abnormal, the width of the skull had decreased resembling a beak-like visceral cranium. With a single administration of 200 mg/kg on day 10 we found a similar but slightly more pronounced outcome. A drastic change of all variables was obtained after eight injections of 100 mg/kg on days 9, 10, and 11. Comparatively we measured maternal plasma concentrations of acyclovir 1 h after the administration of 50, 100 or 200 mg/kg body wt. After an injection of 50 mg/kg on days 9, 10, and 11 of gestation (three injections/day) the plasma levels ranged from 19.1 to 40.0 mg/l (1 mg/l = 4.44 microM). No cumulation was observed. In contrast, a cumulative effect was detected following a dose of 100 mg/kg. After the first injection of this dose a mean value (+/- SD) of 60.3 +/- 14.7 mg/l (n = 16) was obtained. In this case a third injection increased the mean plasma level to 124.6 +/- 16.6 mg/l (n = 5). Further injections, however, led to decreasing levels. One hour after administration of 200 mg/kg body wt acyclovir levels ranged from 120.0 to 163.9 mg/l. We conclude that acyclovir, at doses leading to plasma concentrations well above the therapeutic level in the dam, interferes with the embryonic development in the rat. Acyclovir induces typical gross structural abnormalities which have been first observed using a whole embryo culture system.

Effects of valproic acid, some of its metabolites and analogues on prenatal development of rats in vitro and comparison with effects in vivo

“…A modified drug application on the basis of pharmacokinetic data in connection with an early evaluation of the embryos (e. g. on day 11.5-16 of pregnancy) may be a promising approach to supplement conventional developmental toxicology studies for important substances. Stahlmann et al (1988) have already demonstrated that this method can reveal embryotoxic effects which were not seen in a typical segment II study.…”

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

“…This system has already proven its usefulness by revealing the teratogenic potential of the nucleoside analogue aciclovir . Although the toxic potential of aciclovir (ACV) had not been detected in routinely performed segment II studies (Moore et al 1983), it was possible with the information obtained from the data in vitro to induce corresponding abnormalities in vivo using a modified schedule for drug application: after treatment on day 10 of pregnancy only the teratogenic effect of ACV was shown in 11.5-and 21-day-old rat fetuses Stahlmann et al 1988).…”

“…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 Abbreviations: VAP: vidarabine-phosphate; GCV: ganciclovir; ddA: 2',3'-dideoxyadenosine; ddC: 2',3'-dideoxycytidine; AZT: zidovudine (= azidothymidine); ACV: aciclovir, acicloguanosine; WEC: whole-embryo culture * Dedicated to Professor Gerhard Zbinden on the occasion of his retirement Offprint requests to: S. Klug (ACV) under identical conditions (Klug et al 1985a;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.…”

Gravidez, Aleitamento e Fármacos em Dermatologia - Tratamento Sistémico

“…79 Apesar de não ser comprovadamente teratogénico em humanos, doses elevadas em modelos animais aumentam o risco de morte fetal e de restrição do crescimento intrauterino. 80 A transferência de aciclovir para o leite materno, resulta em concentrações de 1-8,5% da dose materna, sendo presumivelmente seguras na amamentação. 7,[81][82][83] Nenhuma teratogenicidade foi demonstrada com a utilização do famciclovir.…”