Weak acids may act as teratogens by accumulating in the basic milieu of the early mammalian embryo.

Among the eleven drugs or chemicals which are well-documented human teratogens, eight (or their main metabolites) are weak acids whereas none is a weak base. Moreover, 23 out of 32 acids tested have been found to be teratogenic in at least one animal species. The acidic property of drugs may therefore be an important determinant of teratogenicity. We demonstrate here that the intracellular pH (pHi) of the mouse and rat embryo is higher than that of maternal plasma, as determined by the relative accumulation of dimethadione. The antiepileptic drug valproic acid and its pharmacologically active unsaturated metabolite accumulate in embryonic tissue to higher concentrations than in maternal plasma, whereas the essentially neutral amide of valproic acid (valpromide) or ethosuximide do not accumulate in the embryo; we further demonstrate in the rat that the pHi of the embryo decreases with advancing gestation; in general agreement with the pH partition hypothesis, the exposure of the embryo to valproic acid also decreases significantly during that period. Furthermore, the amides of two weak acid teratogens, valpromide and methoxyacetamide, and the imide ethosuximide, are much less teratogenic than their acid counterparts. Our results suggest that weakly acidic drugs, by virtue of their physico-chemical nature, accumulate in the early embryo with its relatively high pHi.