Placental and blood-brain barrier transfer following prenatal and postnatal exposures to neuroactive drugs: relationship with partition coefficient and behavioral teratogenesis.
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.
Watanabe
T
T
Drug Safety Research Center, Daiichi Pharmaceutical Company, Ltd., Tokyo, Japan.
Matsuhashi
K
K
Takayama
S
S
D000818:Animals; D014150:Antipsychotic Agents / Q000493:pharmacokinetics / Q000633:toxicity; D001337:Autonomic Agents / Q000493:pharmacokinetics / Q000633:toxicity; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000187:drug effects*; D005260:Female; D008431:Maternal-Fetal Exchange / Q000502:physiology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D051381:Rats; D012995:Solubility
D014150:Antipsychotic Agents; D001337:Autonomic Agents