Pharmacokinetic determinants of embryotoxicity in rats associated with organic acids.

We have studied four organic acids of similar structure to further understand the basis of their developmental toxicity. Valproic acid (2-propyl pentanoic acid), ethylhexanoic acid, and octanoic acid are isomeric C8 organic acids but their teratologic potency varied widely. Valproic acid induced a moderate to severe teratologic outcome after a single oral administration of 6.25 mmoles/kg on day 12 of rat pregnancy. Twice as much ethylhexanoic acid (12.5 mmoles/kg) induced a less severe response. Octanoic acid was nonteratogenic even at the very high dose of 18.75 mmoles/kg. This latter result is undoubtedly due to poor intestinal absorption of octanoic acid, as the maternal plasma levels never reached half of those measured for valproic acid and ethylhexanoic acid. Moreover, only a tiny fraction of that in maternal plasma was actually transferred into the embryo. On the other hand, the peak concentration and duration of exposure to valproic acid and ethylhexanoic acid were very similar despite a more severe teratologic outcome following valproic acid, which indicated higher intrinsic activity of this latter agent. A fourth agent, methylhexanoic acid, was also studied and had no teratogenic effects when given at 14.1 mmoles/kg. Pharmacokinetic studies of this agent revealed higher peak concentrations in maternal plasma and embryo than valproic acid or ethylhexanoic acid, but the duration of exposure was shorter. We conclude that pharmacokinetic parameters can be important determinants of teratologic outcome and thereby help explain differing potencies of structurally similar chemicals.