Watanabe T, Matsuhashi K, Takayama S
Drug Safety Research Center, Daiichi Pharmaceutical Company, Ltd., Tokyo, Japan.
Toxicol Appl Pharmacol. 1990 Aug;105(1):66-77. doi: 10.1016/0041-008x(90)90359-3.
In order to determine the neurotoxicity of prenatal and postnatal exposures to neuroactive drugs in developing rats, we examined placental and blood-brain barrier (BBB) transfers of these radiolabeled drugs when they were administered sc to pregnant rats on Day 19 of gestation, and to pups on Days 2, 7, and 14 after birth. The logarithms of partition coefficients (log Pcorr), used as indices of the lipid solubility of the drugs, decreased in the order propranolol greater than chlorpromazine greater than haloperidol greater than atropine greater than reserpine greater than dopamine greater than epinephrine greater than norepinephrine. The coefficients of correlation between log Pcorr and BBB transfer were statistically significant in all dams, fetuses, and pups. Propranolol, chlorpromazine, and haloperidol, having high lipid solubility, passed rapidly into fetuses. Behavioral teratogenesis occurred to a greater extent with postnatal than with prenatal exposures. All moderately and poorly lipophilic drugs transferred into fetuses, although at lower plasma concentrations than in dams. BBB transfer was low in dams, fetuses, and pups. The behavioral teratogenic potential of these drugs was relatively weaker than that of highly lipophilic drugs. Our results suggest that BBB transfer of drugs, which varies according to lipid solubility, is a major factor in behavioral teratogenesis. Highly lipid-soluble drugs were readily incorporated into developing rat brains, becoming strongly behaviorally teratogenetic by impairing postnatal functional maturation.
为了确定发育中大鼠产前和产后接触神经活性药物的神经毒性，我们检测了这些放射性标记药物在妊娠第19天皮下注射给怀孕大鼠，以及在出生后第2天、第7天和第14天皮下注射给幼崽时的胎盘和血脑屏障（BBB）转运情况。用作药物脂溶性指标的分配系数对数（log Pcorr）按以下顺序降低：普萘洛尔＞氯丙嗪＞氟哌啶醇＞阿托品＞利血平＞多巴胺＞肾上腺素＞去甲肾上腺素。log Pcorr与BBB转运之间的相关系数在所有母鼠、胎儿和幼崽中均具有统计学意义。脂溶性高的普萘洛尔、氯丙嗪和氟哌啶醇迅速进入胎儿体内。产后暴露比产前暴露更容易发生行为致畸。所有中度和亲脂性差的药物都能进入胎儿体内，尽管其血浆浓度低于母鼠。母鼠、胎儿和幼崽的BBB转运率较低。这些药物的行为致畸潜力相对低于高度亲脂性药物。我们的结果表明，药物的BBB转运因脂溶性而异，是行为致畸的主要因素。高度脂溶性药物很容易进入发育中的大鼠大脑，通过损害产后功能成熟而产生强烈的行为致畸作用。
