The long term goal of our investigations is to improve on the treatment of the pregnant opiate addict and the outcome of their newborns. For several decades, the only treatment available for these patients were methadone programs. These programs have been successful and methadone became the """"""""standard"""""""" for treating the heroin and morphine addict. However, relapses, side effects, drug interactions and unexplained clinical observations were reported and prompted investigators to seek alternative drugs. Two such drugs, buprenorphine (BUP) and L-acetylmethadol (LAAM) are currently available but data on their effects on the pregnant patient and her newborn are scarce to non-existent. The goal of this investigation is to provide the needed basic information on BUP and LAAM for their safe use in treatment of the pregnant opiate addict as well as help understand several unexplained observations associated with these patients and their newborns in methadone programs. The hypothesis for our investigation is that the three opiates, because of their physicochemical properties, may be transported by passive diffusion across the placenta from the maternal to fetal circulation. However, human placenta plays an important role in protecting the fetus from exposure to drugs, xenobiotics and environmental pollutants. This role can be achieved either by metabolizing the drug or extruding it to the maternal circulation by the transporter P-glycoprotein (P-gp). Our data will determine if either of these functions affects the transfer of these opiates to the fetal circulation. The technique of dual perfusion of human placental lobule will be utilized to obtain these data. The placentas utilized will be obtained from full term healthy pregnancies.
The specific aims for the proposed work are: (1) Determine the transplacental transfer (TPT) parameters for BUP, LAAM and methadone. (2) Determine the metabolites formed for each opiate by placental tissue and their subsequent distribution between the tissue, maternal and fetal circulations. (3) Identify which of the opiates is a substrate for P-gp. Data obtained may provide the cause for several unexplained clinical observations associated with treatment of this patient population. These include: withdrawal symptoms, and severity, observed in some but not all newborns for mothers treated with BUP or methadone during pregnancy; lack of correlation between dose of the drug and its maternal serum levels; lower concentrations of the opiate and metabolites in pregnant than non-pregnant patients. Identification of the opiate substrate for P-gp will allow avoiding drug interactions with other medications thus avoiding fetal over exposure to both. In summary, the information obtained will provide a better understanding of the transfer of these opiates across human placenta and the role of the tissue in decreasing fetal exposure to the drugs. It may also provide a choice of medications for treating an individual patient according to her condition thus improving neonatal outcome.
| Hemauer, Sarah J; Nanovskaya, Tatiana N; Abdel-Rahman, Sherif Z et al. (2010) Modulation of human placental P-glycoprotein expression and activity by MDR1 gene polymorphisms. Biochem Pharmacol 79:921-5 |
| Hemauer, Sarah J; Patrikeeva, Svetlana L; Nanovskaya, Tatiana N et al. (2010) Role of human placental apical membrane transporters in the efflux of glyburide, rosiglitazone, and metformin. Am J Obstet Gynecol 202:383.e1-7 |
| Nanovskaya, Tatiana N; Bowen, Robin S; Patrikeeva, Svetlana L et al. (2009) Effect of plasma proteins on buprenorphine transfer across dually perfused placental lobule. J Matern Fetal Neonatal Med 22:646-53 |
| Hemauer, Sarah J; Patrikeeva, Svetlana L; Nanovskaya, Tatiana N et al. (2009) Opiates inhibit paclitaxel uptake by P-glycoprotein in preparations of human placental inside-out vesicles. Biochem Pharmacol 78:1272-8 |
| Moody, David E; Lin, Shen-Nan; Chang, Yan et al. (2008) An enantiomer-selective liquid chromatography-tandem mass spectrometry method for methadone and EDDP validated for use in human plasma, urine, and liver microsomes. J Anal Toxicol 32:208-19 |
| Nanovskaya, Tatiana N; Nekhayeva, Ilona A; Hankins, Gary D V et al. (2008) Transfer of methadone across the dually perfused preterm human placental lobule. Am J Obstet Gynecol 198:126.e1-4 |
| Zharikova, Olga L; Deshmukh, Sujal V; Kumar, Meena et al. (2007) The effect of opiates on the activity of human placental aromatase/CYP19. Biochem Pharmacol 73:279-86 |
| Nekhayeva, Ilona A; Nanovskaya, Tatiana N; Hankins, Gary D V et al. (2006) Role of human placental efflux transporter P-glycoprotein in the transfer of buprenorphine, levo-alpha-acetylmethadol, and paclitaxel. Am J Perinatol 23:423-30 |
| Zharikova, Olga L; Deshmukh, Sujal V; Nanovskaya, Tatiana N et al. (2006) The effect of methadone and buprenorphine on human placental aromatase. Biochem Pharmacol 71:1255-64 |
| Nanovskaya, Tatiana; Nekhayeva, Ilona; Karunaratne, Nedra et al. (2005) Role of P-glycoprotein in transplacental transfer of methadone. Biochem Pharmacol 69:1869-78 |
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