MATERNAL/FETAL PHARMACOKINETICS AND PHARMACODYNAMICS

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The overall goal of this component is to identify opioid peptide analogs that are analgesic and have no adverse effects on the mother or fetus. This goal can be accomplished by finding peptide analogs that do not cross the placenta and have minimal maternal effects. Alternatively, it may be possible to find peptides that cross the placenta but have no significant maternal or fetal effects. Over the past two years, we have been able to identify certain synthetic opioid peptide analogs that have limited distribution across the placenta and little adverse effects in the fetus. However, our findings have also led us to re-assess our hypotheses, and guides us to a number of modifications in our approach to the next five years of this project. Our pharmacodynamic results with two mu agonists (DAMGO and DALDA) showed significant effects on maternal cardiovascular function after iv bolus infection but little adverse effect on the fetus. We hypothesize that these potentially adverse opioid effects may be minimalized by continuous iv infusion or intrathecal (it) administration. Our pharmacodynamic results with two delta opioid peptide analogs (DPDPE and DELT) showed significant cardiovascular and respiratory effects in the mother that are not mediated by opioid receptors, as well as significant adverse effects on the fetus. We hypothesize that delta opioid peptide analogs that do not possess these non-opioid effects may be ideal drugs for systemic administration. The specific aim of this component is therefore to carry out a systematic investigation of the pharmacokinetics and pharmacodynamics of mu and delta opioid peptide analogs in the maternal-fetal unit. Our first specific aim is to determine the antinociceptive action of these mu and delta opioid peptide analogs when administered iv and it in the rodent. Our second specific aim is to determine the pharmacokinetics of novel mu and delta opioid peptide analogs in non-pregnant and pregnant sheep after iv and it administration and determine the extent of fetal drug exposure. Our third specific aim is to examine the effects of mu and delta opioid peptide analogs on cardiovascular, respiratory and metabolic function in non-pregnant, pregnant and fetal sheep after iv and it administration, and determine whether any of the effects are mediated by opioid receptors. The specific aims proposed in this Component will be carried out jointly by Dr. Szeto and Dr. Clapp in their respective laboratories. The strength of this component is the combined pharmacokinetic-pharmacodynamic approach being carried out in the same animal model. This Component will play an integral role in achieving the overall goal of the PPG.