The effects of different chemical forms of a test compound on embryotoxicity, distribution and metabolism in vitro.
The lipoxygenase inhibitor N-hydroxy-N-methyl-7-propoxy-2-naphthalenethanamine (QA 208-199) was tested in vitro for its general embryotoxicity and, in particular, for its teratogenic potential. QA 208-199 was either added as the base (QA-base) or as its citric acid salt (QA-citrate) and its effects were compared with the effects of the salt, sodium citrate (Na-citrate). In addition, the main in vivo metabolite 209-668 (QA-acid) was tested. The in vitro no-effect levels of QA-base and QA-citrate on embryonic growth, differentiation and morphology were dependent on the chemical form of the compound added to the culture medium as well as on the use of a drug-activating system (S-9 mix). QA-acid and Na-citrate were not embryotoxic in vitro up to the highest concentration tested. The metabolites formed in the culture medium after the addition of QA-base or QA-citrate were quantitatively and qualitatively limited. After embryo cultivation in the presence of QA-acid, no metabolites could be detected in the yolk-sac and embryonic tissue. QA-acid by itself was stable in the culture. In contrast, in yolk-sac and embryonic tissues grown in the presence of QA-base or QA-citrate, no QA-base was detected at the end of the culture period, but high levels of QA-acid and of two unknown metabolites M5 and M6 were measured. The tissue concentrations found for these metabolites correlated with the extent of the observed embryotoxicity under the different culture conditions. It can be concluded that varying in vitro embryotoxic responses could be obtained depending on the chemical form of the test compound added to the culture. Furthermore, these effects could be enhanced by co-incubation with an activating system (S-9 mix). By measuring drug and metabolic levels in the culture medium and tissues during and at the end of the culture period it was possible to determine, in part, the mode of the in vitro embryotoxic action of QA 208-199.
Bechter
R
R
Toxicology Department, Drug Safety Assessment, Sandoz Ltd, CH-4002 Basel, Switzerland.
Brouillard
J F
JF