Teratogenicity in vitro-A comparative study of four antimycotic drugs using the whole-embryo culture system.
The embryotoxic effects caused in vitro by the four antimycotic compounds griseofulvin, ketoconazole, naftifine and terbinafine were compared. Rat embryos (9.5 days old) were cultivated in rat serum for 48 hr both in the presence and in the absence of the individual test compounds. A rat liver microsomal preparation and NADPH were added to the cultures. Effects on growth and differentiation were evaluated and dysmorphogenic effects on various embryonic features were recorded. The compounds could be ranked as follows: in terms of the concentrations that affected growth in vitro, griseofulvin = naftifine = ketoconazole < terbinafine, and, with regard to retarded differentation, griseofulvin = ketoconazole = naftifine < terbinafine, while for morphological findings, ketoconazole < griseofulvin = naftifine < terbinafine. The ratio between the concentration affecting rat embryonic morphology in vitro and the human peak plasma levels after multiple drug application was approximately 0.2 for ketoconazole, 3 for griseofulvin, 20 for terbinafine and 2000 for naftifine. The results of this study verified that this in vitro system can be used to classify test compounds according to their embryotoxic effects. The findings reported here were in agreement with those of in vivo studies. In both systems, ketoconazole and griseofulvin had relatively high teratogenic potential and terbinafine and naftifine had none.
Bechter
R
R
Sandoz Ltd, Preclinical Research, Toxicological Department, CH-4002 Basel, Switzerland.
Schmid
B P
BP