Embryo-maternal distribution of basic compounds in the CD-1 mouse: doxylamine and nicotine.
The intracellular pH of the early postimplantation rodent embryo (pHi) is alkaline with respect to the corresponding plasma of the pregnant dam. This transplacental pH gradient is of considerable importance in the accumulation of teratogenic weak acids by the embryo. The importance of pH in the partitioning of basic drugs across the early mammalian placenta has not been investigated. Theoretically, the maternal plasma should retain a higher concentration of basic drugs than the embryo due to a greater degree of drug ionization in the more acidic plasma. To explore the significance of pH partitioning upon the transplacental distribution of basic compounds, two bases, doxylamine and nicotine, were administered to pregnant CD-1 mice during early organogenesis. The maternal plasma and embryonic concentrations of the bases were measured and the resulting embryo/maternal plasma (E/P) ratio was calculated and compared to the ratio predicted by the Henderson-Hasselbalch equation. Following ip injection of nicotine on Day 9 of gestation, the E/P ratio was significantly greater than the predicted ratio 10 min after injection and continued to rise for 3 hr. For doxylamine succinate administered by oral gavage on Day 9 or 10, the E/P ratio was also significantly greater than the ratio predicted from the pH gradient. Our results indicate that the partitioning of these basic compounds between the maternal plasma and the early postimplantation rodent embryo is not a consequence of the pH gradient between the two compartments alone.
Roberts
L G
LG
Division of Reproductive and Developmental Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079.
Luck
W
W
Holder
C L
CL
Scott
W J
WJ
Nau
H
H
Slikker
W
W
D000818:Animals; D001692:Biological Transport; D004319:Doxylamine / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D006863:Hydrogen-Ion Concentration; D008431:Maternal-Fetal Exchange; D051379:Mice; D008815:Mice, Inbred Strains / Q000196:embryology; D009132:Muscles / Q000378:metabolism; D009538:Nicotine / Q000097:blood / Q000493:pharmacokinetics*; D011247:Pregnancy; D011725:Pyridines / Q000493:pharmacokinetics*; D013997:Time Factors
D011725:Pyridines; D009538:Nicotine; D004319:Doxylamine; C035385:doxylamine succinate