Sex differences in the response of rats to pentobarbital sodium: IV. Pentobarbital levels in pregnant and nonpregnant rats

Abstract

1.1. Pentobarbital disappears from the blood of pregnant rats relatively more slowly than from the blood of nonpregnant females. From the eighth through the twelfth hour after injection the blood level remains significantly higher in the pregnant animal.2.2. Brain levels remain significantly higher in the pregnant rat from the sixth hour. Two to 4 hours after injection fetal brain levels are 90 per cent of maternal values and up to 12 hours fetal levels remain approximately 75 per cent of that of the mother.3.3. Similarly, the drug level remains higher in the liver of the pregnant rat than in the nonpregnant rat. Fetal liver has a slightly higher affinity for barbiturate than does the fetal brain. It is doubtful, however, that the fetal rat liver contains enzymes capable of detoxifying the drug.4.4. Pentobarbital is also present in small amounts in amniotic fluid, but its disappearance from this site is slower than from the fetal tissues.5.5. Thus, when the nonpregnant female is given drug, the brunt of detoxification falls upon the liver at once. The respiratory, circulatory, and temperature regulatory mechanisms are severely depressed until detoxification is achieved within a few hours, and the drugged rat awakens relatively early.6.6. In the pregnant rat, on the other hand, the liver does not receive the full burden of the drug as rapidly. It crosses the placental barrier and pools in fetal tissues and in amniotic fluid, only to be fed back into maternal tissues gradually. The fetal tissues play no role in detoxification, but merely serve to decrease the load thrown upon the mother at one time. Thus, maternal barbiturate levels remain high and sleep is prolonged.7.7. In light of the higher barbiturate levels in pregnancy, the failure of the pregnant rat to become as severely depressed as the nonpregnant female remains enigmatic. A possible cause could lie in alterations of protein-binding in pregnancy.8.8. Two unknowns remain to be solved: (1) Is the assumption that fetal rats are incapable of detoxifying barbiturate valid as in neonatal rabbits, guinea pigs, and mice? (2) To what degree is protein-binding of pentobarbital altered in pregnancy?