Medications Development for the Pregnant Opiate Addict

我们研究的长期目标是为治疗糖尿病的药物开发做出贡献。 从而改善产妇和新生儿的结果。这将通过获得 关于美沙酮和丁丙诺啡（BUP）人体胎盘生物处置的信息。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。最近 来自我们实验室的数据表明，两种阿片类药物的胎盘转移动力学受其 通过细胞色素P450 19（CYP 19）代谢和通过转运蛋白P糖蛋白（P-gp）流出。的 这项建议的重点是研究遗传多态性和代谢变构底物对 CYP 19和P-gp活性及外排转运体乳腺癌耐药蛋白的作用 _BCRP）对妊娠期间BUP和美沙酮生物处置的影响。假设是：“ l acental metabo！！c酶和efflux转运蛋白取决于胎龄，并在遗传和 代谢控制目前的知识表明，以下因素可能影响胎盘的生物处置， 暴露于BUP和美沙酮：BUP和美沙酮经胎盘转运的动力学研究 足月胎盘与足月时不同。胎盘组织中芳香化酶和P-gp的活性受胎盘组织中 notype和胎龄。孕酮是P-gp活性的变构调节剂。BCRP表达 胎盘中的蛋白质含量高于其他任何人体组织。因此，将研究以下具体目标 利用胎盘小叶和滋养层组织亚细胞组分双重灌注技术。 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.确定影响的 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)识别 在孕龄早期负责代谢美沙酮和BUP的酶。(13)确定 CYP 19基因型与其活性的关系6.确定BUP和美沙酮对 妊娠期间通过CYP 19生物合成雌激素（雌酮、雌二醇和雌三醇）。总之， 获得的信息将有助于更好地了解影响胎儿暴露于BUP的因素， 因此，改善了正在接受治疗的阿片类药物成瘾早产儿的新生儿结局。

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.