Studies on the pharmacological bases of fetal toxicity of drugs (IV). Effect of endotoxin and starvation on serum protein binding of salicylic acid in pregnant rats.

Our previous paper reported that the fetotoxic effects of aspirin (ASA) were enhanced by bacterial endotoxin (LPS), and the effects of ASA were attributed to its major metabolite, salicylic acid (SA), as indicated by high SA concentrations in fetus and placenta. In order to clarify the mechanisms of the enhancement by LPS, serum total protein, albumin and free fatty acid (FFA) levels and SA-binding capacity of serum protein were investigated in pregnant rats. The following results were obtained: 1) FFA levels increased steadily after day 16 of pregnancy, and SA-binding capacity of serum protein decreased gradually after day 18, as the pregnancy proceeded to full term. 2) LPS injection decreased total protein and albumin levels in normal and starved rats on day 15 of pregnancy. 3) Starvation and/or LPS injection potentiated the increase of FFA level and reduced significantly SA-binding capacity of serum protein in the rats on day 15 of pregnancy. 4) Serum protein showing low SA-binding capacity from LPS-treated rats recovered normal SA-binding capacity when FFA was removed from serum protein by charcoal treatment. These data suggested the decrease of the SA-protein binding in serum by the increased level of FFA, an inhibitor of the binding, and the decreased level of albumin as a possible mechanism for the potentiation of the fetotoxicities of ASA by LPS.