Medications Development for the Pregnant Opiate Addict

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l'he long-term goal of our investigations is to contribute to the development of medications for treatment of the _regnant opioid addict thus improving maternal and neonatal outcome. This will be achieved by obtaining information on human placental bio-disposition of methadone and buprenorphine (BUP). Methadone and BUP _re used for treatment of the opioid addict but only methadone is approved in the US for the pregnant. Recent data from our laboratory indicate that the kinetics for placental transfer of the two opioids is affected by their metabolism by Cytochrome P450 19 (CYP19) and their efflux by the transporter P glycoprotein (P-gp). The focus of this proposal is to investigate the effect of genetic polymorphism and metabolic allosteric substrates on Ihe activity of CYP19 and P-gp as well as the role of the efflux transporter breast cancer resistance protein _BCRP) on the bio-disposition of BUP and methadone during pregnancy. The hypothesis is: "The activity of l acental metabo!!c enzymes and effiux transporters depends on gestational age and is under genetic and etabolic control . Current knowledge suggests that the following could affect placental bio-disposition of, and al exposure to, BUP and methadone: The kinetics for transplacental transfer of BUP and methadone in eterm placentas is different from that at term. The activity of aromatase and P-gp are affected by placental notype and gestational age. Progesterone is an allosteric regulator of P-gp activity. BCRP expression in placenta is higher than in any other human tissue. Therefore, the following specific aims will be investigated atilizing the technique of dual perfusion of placental lobule and subcellular fractions oftrophoblast tissue. 1. Determine the kinetic parameters for transfer of methadone and BUP in preterm placentas. 2. Determine the relation between P-gp genotype and its activity in the efflux of BUP and methadone. 3. Determine the effect of progesterone, the allosteric substrate of P-gp, on its activity in the efflux of BUP and methadone. 4. Determine the role of breast cancer resistance protein (BCRP) in the efflux of BUP and methadone. 5. (A) Identify the enzyme responsible for the metabolism of methadone and BUP at earlier gestational ages. (13) Determine the relation between CYP19 genotype and its activity. 6. Determine the effects of BUP and methadone on the biosynthesis of estrogens (estrone, estradiol and estriol) by CYP19 during pregnancy. In summary, the information obtained will result in a better understanding of the factors affecting fetal exposure to BUP and methadone during pregnancy thus irnproving the neonatal outcome of the premaant opioid addict being treated.