Physiologically based pharmacokinetics of methoxyacetic acid: dose-effect considerations in C57BL/6 mice.

Abstract

Methoxyacetic acid (MAA), a weak acid with a pKa of 3.57, was used to test the broad hypothesis that distribution of weak acids in maternal and fetal tissues is determined principally by the pKa of the acid and the pH values of tissue and fluid compartments and to examine tissue dose-teratogenesis relationships, as well as administered dose-teratogenesis relationships. Five related experimental studies were conducted in pregnant C57BL/6CrIBR mice: a conventional dose-response study of developmental toxicity and transplacental pharmacokinetics in mice, a second dose-response study in which reproductive outcomes in litters from individual dams were related to individual pharmacokinetic behavior, a protein-binding experiment, an embryo tissue localization study, and determination of pH in maternal and embryonic compartments after exposure to MAA. MAA was administered intraperitoneally at 9:00 a.m. on day 10 of gestation, at doses ranging from 88 to 164 mg/kg. Localization within the forelimb bud of the embryo, an MAA target site, was determined by computerized image analysis of the distribution of radiolabeled MAA. The kinetic predictions of a physiologically based model incorporating tissue pH values and MAA pKa agreed well with observed concentrations at the lowest dose. However, at intermediate and higher doses, concentrations in both maternal and embryonic tissues were consistently underestimated. MAA was bound neither to maternal plasma proteins nor to embryonic proteins. Intermediate and higher doses of MAA caused dose-dependent transient depressions in tissue pH, but these were not of sufficient duration to bring predicted tissue concentrations into congruence with the concentrations observed. Distribution of MAA within the forelimb bud was broadly consistent with the pH hypothesis, but MAA concentration was not increased in the distal postaxial sector that is the site of the precursor cells of the missing digits. Internal exposure to MAA, defined as the area under the maternal plasma or embryo concentration curve (AUC), was not proportional to administered dose, but AUC-response relationships generated by the group and individual dose-response studies were comparable. While AUC may be a useful measure of effective MAA dose, it cannot be accurately predicted at teratogenic doses of this agent by the model as it is presently structured.