Medications Development for the Pregnant Opiate Addict

描述(由申请人提供)：我们研究的长期目标是帮助开发治疗怀孕阿片成瘾者的药物，从而改善孕产妇和新生儿的结局。这将通过获得关于人类胎盘生物处置美沙酮和丁丙诺啡(BUP)的信息来实现。美沙酮和BUP用于治疗阿片类药物成瘾者，但在美国，只有美沙酮被批准用于孕妇。我们实验室的最新数据表明，这两种阿片类药物的胎盘转运动力学受细胞色素P45019(CyP19)代谢和P-糖蛋白转运体(P-gp)外排的影响。本研究的重点是探讨基因多态和代谢变构底物对细胞色素P19和P-糖蛋白活性的影响，以及外排转运体乳腺癌耐药蛋白(BCRP)在孕期BUP和美沙酮生物处置中的作用。假说是：“胎盘代谢酶和外排转运蛋白的活性取决于胎龄，并受遗传和代谢控制。”目前的研究表明，以下因素可能影响胎盘对BUP和美沙酮的生物处置和暴露：早产儿胎盘中BUP和美沙酮经胎盘转移的动力学与足月胎盘不同。芳香酶和P-糖蛋白活性受胎盘基因和胎龄的影响。孕酮是P-gp活性的变构调节剂。BCRP在胎盘中的表达高于任何其他人类组织。因此，利用胎盘小叶和亚细胞部分滋养层组织的双重灌流技术，将研究以下特定的目的。1.测定美沙酮和BUP在早产胎盘中转运的动力学参数。2.确定P-gp基因与BUP和美沙酮外排中P-gp活性的关系。3.测定P-gp的变构底物孕酮对其在BUP和美沙酮外排中活性的影响。4.确定乳腺癌耐药蛋白(BCRP)在BUP和美沙酮外流中的作用。5.(A)确定在妊娠早期负责美沙酮和BUP代谢的酶。(13)确定CYP19基因分型与其活性的关系。6.测定BUP和美沙酮对孕期细胞色素P19合成雌激素(雌酮、雌二醇和雌三醇)的影响。总之，所获得的信息将有助于更好地了解怀孕期间影响胎儿接触BUP和美沙酮的因素，从而改善正在接受治疗的怀孕阿片成瘾者的新生儿结局。

DESCRIPTION (provided by applicant): The long-term goal of our investigations is to contribute to the development of medications for treatment of the pregnant 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 are 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 the 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 placental metabolic enzymes and efflux transporters depends on gestational age and is under genetic and metabolic 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 preterm placentas is different from that at term. The activity of aromatase and P-gp are affected by placental genotype 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 utilizing the technique of dual perfusion of placental lobule and subcellular fractions trophoblast 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 improving the neonatal outcome of the pregnant opioid addict being treated.