Murine teratology and pharmacokinetics of the enantiomers of sodium 2-ethylhexanoate.
A mouse model for the induction of exencephaly with sodium (+/-)-2-ethylhexanoate has been developed using multiple administration regimes. With three consecutive administrations at one-half-day intervals, the most sensitive time to induce exencephaly was Gestational Days 8-9. Using the racemic substance it was determined that the SWV strain was more sensitive to the induction of exencephaly than the C57BL/6NCrlBR strain. The enantiomers of 2-ethylhexanoic acid were separated via preparative HPLC to greater than 99.8% optical purity, and greater than 99% purity according to a gas chromatographic analysis. It was demonstrated that the (R)-enantiomer is a more potent teratogen than the (S)-enantiomer for the induction of exencephaly as well as malformations of other organ systems. Pharmacokinetic analyses for each of the enantiomers were performed in maternal plasma, maternal muscle, and embryo. The pharmacokinetics showed that the peak concentration (Cmax) for both enantiomers in the three compartments was approximately equivalent and was attained within 15 min following the third administration. The area under the concentration versus time curve values for the two enantiomers were approximately 10% higher for the (R)-antipode because of a slightly slower elimination of this compound. There was negligible (or no) racemization of the two enantiomers in the biological samples. The results suggest that teratologic differences in the enantiomers of sodium 2-ethylhexanoate are not due to differences in the concentrations of these antipodes in the embryo, but more likely result from the specific interaction of the enantiomers with chiral molecules in the embryo.
Collins
M D
MD
Institute of Toxicology and Embryopharmacology, Free University Berlin, Germany.
Scott
W J
WJ
Miller
S J
SJ
Evans
D A
DA
Nau
H
H
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D002208:Caproates / Q000493:pharmacokinetics* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000187:drug effects; D005260:Female; D005313:Fetal Death / Q000139:chemically induced; D005865:Gestational Age; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009436:Neural Tube Defects / Q000139:chemically induced; D011247:Pregnancy; D012886:Skull / Q000002:abnormalities; D013237:Stereoisomerism; D013723:Teratogens / Q000493:pharmacokinetics* / Q000633:toxicity
D002208:Caproates; D013723:Teratogens; C040668:2-ethylhexanoic acid