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Project 3

Project 3: Role of OCT3 in Drug Pharmacokinetics During Pregnancy.
PI: Vadivel Ganapathy, Ph.D.

Project 3 deals with the proteins known as the Organic Cation Transporter 3 (OCT3), which is present in the placenta at very high levels. OCT3 interacts with a wide variety of drugs (e.g. antidepressants). This study suggests that this particular placental transporter may:

  • metabolize these drugs and thus protect the fetus from the drugs’ effects, or
  • transfer these drugs to the fetus and thus expose the fetus to the drugs’ effects
  • affect the concentrations of these drugs in mother’s blood during pregnancy.

To address these questions, we propose the following specific aims:

  • Investigate the expression and membrane localization of OCT3 in human placentae at different gestational ages.
  • Compare the polarized expression of OCT3 in placental syncytiotrophoblast with that in renal tubular cells and intestinal epithelial cells.
  • Investigate the substrate specificity of the OCT3 using two different functional expression systems (mammalian cell expression and Xenopus laevis oocyte expression), with special emphasis on the overlap between OCT3 and P-glycoprotein in terms of handling of therapeutic drugs.
  • Study the influence of pregnancy on the expression of OCT in the intestine, kidney and liver in mice and in nonhuman primates. Compare the fetal exposure and/or pharmacokinetics of OCT3-specific therapeutic drugs under pregnant and non-pregnant states between control and OCT3 knockout mice.
  • Investigate the regulation of OCT3 expression by steroid hormones, with special emphasis on progesterone and potential involvement of the type 1 sigma receptor, using human cell lines.
  • Investigate the regulation of OCT3 expression by the human immunodeficiency virus transactivator protein Tat using human cell lines stably transfected with HIV-Tat cDNA and also using Tat-expressing transgenic mice. Compare the fetal exposure and/or pharmacokinetics of OCT3-specific therapeutic drugs under pregnant and non-pregnant states between control mice and Tat-expressing transgenic mice.