The long-range goal of this portion of the PPG is to define the pharmacokinetics of synthetic opioid peptide analogs in late pregnancy using the chronically-catheterized pregnant ewe model.
The specific aims for the initial five years of the project will focus in five areas: 1) to determine the effects of pregnancy on the pharmacokinetics of synthetic opioid peptide analogs; 2) to determine the extent of fetal exposure to synthetic opioid peptide analogs with different physiological characteristics; 3 ) to determine the transplacental and nonplacental clearances of these peptide analogs in mother and fetus; 4) to compare the extent of fetal exposure to opioid peptide analogs after maternal intravenous and epidural administration; and 5) to determine the effects of intravenous and epidural administration of opioid peptide analogs on blood pressure, heart rate, plasma glucose, lactate and cortisol levels in both nonpregnant and pregnant sheep. Maternal and fetal plasma levels of the peptide analogs will be assayed using mass spectrometry in Dr. Desiderio's laboratory. These data will be used to test the first general hypothesis of the PPG, namely that placental transfer of opioid peptide analogs will be determined by their physicochemical characteristics, and their transfer will be more limited compared to opiate alkaloids. The proposed studies will provide new and clinically-relevant information on the effects of pregnancy and route of administration of peptide pharmacokinetics. In addition, these studies will contribute to our understanding of the physicochemical characteristics which favor the transfer of peptides across the placenta, dura and blood-brain barrier. Finally, the plasma concentration-response data will provide new information on the effects of pregnancy on opioid actions, as well as aid in dose selection for the maternal-fetal pharmacodynamic studies.
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