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促进开发用于治疗妊娠阿片类药物成瘾的药物，从而改善孕产妇和新生儿结局。这将通过获得美沙酮和丁丙诺啡（BUP）在人胎盘中的生物分布信息来实现。美沙酮和BUP用于治疗阿片类药物成瘾，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移动力学受细胞色素P450 19（CYP 19）代谢和转运蛋白P糖蛋白（P-gp）外排的影响。本提案的重点是研究遗传多态性和代谢变构底物对CYP19和P-gp活性的影响，以及外排转运蛋白乳腺癌耐药蛋白（BCRP）对妊娠期间BUP和美沙酮生物处置的作用。假设是：“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”。目前的知识表明，以下可能会影响胎盘的生物处置，以及所有暴露于，BUP和美沙酮：在早产胎盘的BUP和美沙酮的经胎盘转移的动力学是不同的，在足月。芳香化酶和P-gp活性受胎盘基因型和胎龄的影响。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体组织。因此，将利用胎盘小叶和亚细胞组分滋养层组织的双重灌注技术研究以下具体目标。1.确定美沙酮和BUP在早产胎盘中转移的动力学参数。2.确定P-gp基因型与BUP和美沙酮外排活性的关系。3.测定孕酮（P-gp的变构底物）对BUP和美沙酮外排活性的影响。4.确定乳腺癌耐药蛋白（BCRP）在BUP和美沙酮外排中的作用。5. (A)确定负责代谢美沙酮和BUP在孕龄早期的酶。(13)确定CYP19基因型与其活性的关系。6.确定BUP和美沙酮对妊娠期间CYP19合成雌激素（雌酮、雌二醇和雌三醇）的影响。总之，所获得的信息将导致更好地了解影响胎儿在妊娠期间暴露于BUP和美沙酮的因素，从而改善正在接受治疗的妊娠阿片类药物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.