The major goal of this research is to understand and hence predict the effect of a maternally administered drug on the fetus from knowledge of drug disposition in pregnancy and the specific effects of the drug and active metabolites on the fetus. Specifically, we seek to understand the effects of maternal morphine administration on the fetus. Systemic opiates are used to provide analgesia for pregnant women. However, concern for depressive effects in the fetus and newborn limits use. Morphine may adversely affect the fetus indirectly by depressing maternal respiratory and cardiovascular function or directly by transfer across the placenta. The overall effect on the fetus may be further complicated by formation of active metabolites. Morphine is biotransformed to morphine-6-glucuronide (M6G) which exerts similar effects to morphine and morphine-3-glucuronide (M3G) which does not bind to the opioid receptor but has profound excitatory effects. Little is known about transfer of these glucuronides across the placenta or the ability of the fetus to form these metabolites. Our overall hypothesis is that the combination of different permeabilities and differential rates of production of M6G and M3G in the mother and fetus leads to a profile of drug and metabolite concentrations in the fetus which gives rise to a distinctive time-course of action and response in the fetus to maternal administration of morphine. It is the interaction of the indirect maternal and direct fetal effects of the three pharmacologic agents rather than the effect of a single agent acting in the fetus that accounts for the overall fetal response.
Our specific aims are to understand how the relationships among placental transfer of morphine, M6G and M3G and the formation of the metabolites within the fetus determine their concentrations in fetal plasma and to relate these concentrations with the response of the fetus.
These aims are carried out using the chronically instrumented pregnant baboon with an integrated approach to the pharmacokinetic and pharmacodynamic studies. The experimental design incorporates dose-kinetics, dose-response and time-action analysis and evaluation of cardiorespiratory and neurobehavioral parameters which have important clinical ramifications for the fetus and neonate. Extrapolations from this research have direct clinical relevance and create a framework for understanding in vitro and nonprimate research.
