THE ENANTIOSELECTIVE TERATOGENICITY OF 2-NORMAL-PROPYL-4-PENTYNOIC ACID (4-YN-VPA) IS DUE TO STEREOSELECTIVE INTRINSIC ACTIVITY AND NOT DIFFERENCES IN PHARMACOKINETICS

The present study was designed to investigate whether there are pharmacokinetic reasons for the enantioselective teratogenicity of R(+)-4-yn-VPA (low potency) and S(-)-4-yn-VPA (high potency). A gas chromatographic method was employed to determine 4-yn-VPA enantiomers in maternal plasma, brain, erythrocytes and in the embryo and decidua/extraembryonic membranes of the mouse following a single intraperitoneal dose of 300 mg/kg (+/-)-4-yn-VPA-Na on day 9 of gestation. Furthermore, the pharmacokinetics of R- and S-4-yn-VPA were studied in maternal plasma of day-8 pregnant mice following intraperitoneal administration of 300 and 500 mg (+/-)-4-yn-VPA-Na/kg body wt%., respectively. No significant difference in the pharmacokinetic profiles of the two enantiomers was detected in either the maternal organism or in the embryonic compartments. Thus, the two enantiomers reach the embryo in comparable concentrations during the sensitive period of organogenesis, but exhibit very different teratogenic activities. This study therefore indicates that the stereoselective teratogenicity of 4-yn-VPA is due to differences in intrinsic activities and not due to differences in the pharmacokinetics of the enantiomers.