Use of the whole-embryo culture system in drug safety assessment?
The embryotoxicity and, in particular, the teratogenic potential of three new drug combinations were investigated. The interactions of the single components (all already on the market) in the different drug mixtures were determined by testing the single components in addition to the drug combinations. In order to evaluate the usefulness of these results for safety assessment, the no-effect concentrations (NEC) of the single compounds or the mixed drug preparations, with respect to embryonic growth and differentiation and the presence of anomalies, were compared with human plasma/serum levels during therapeutic use. In addition, in vivo animal data of the single components were used to put into perspective the NEC values after direct in vitro exposure of embryos. Embryotoxicity, measured as a retardation of growth and of differentiation, as well as an increased percentage of cultured embryos with morphological abnormalities, was present at concentrations of 100 mug/ml for the preparation KT 1/300 (ketotifen/theophylline). These effects could be attributed to the component theophylline, as ketotifen was free of an embryotoxic/teratogenic potential in vitro. In the case of the compound mix VKB/BQ, a combination of pindolol, clopamide and endralazine, the in vitro effects of the mixture on embryonic development could also be attributed to one of the compounds (pindolol) in the mixture. In the case of HYCT 4520, the effects of the components hydergine (co-dergocrine mesylate), clopamide and triamterene on embryonic growth, differentiation and anomalies were additive in the drug mixture. None of the compounds was reported to be associated with human teratogenicity. The NEC of the components in the whole-embryo culture system, tested either as a mixture or as individual compounds, were higher than the human peak plasma levels measured during therapeutic use of the compounds. In addition, the single components were reported to be non-teratogenic in in vivo teratogenicity studies up to doses many times higher than the therapeutic dose levels in humans. This study illustrates the usefulness of the whole-embryo culture system as a suitable tool for investigating the embryotoxicity/teratogenicity potential of newly registered drug combinations and the synergistic effects of their single components as part of registration toxicology.
Bechter
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Toxicology Department, Drug Safety Assessment, Sandoz Ltd, CH-4002 Basel, Switzerland.
Schön
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