The aim of this project is to understand the role of OCT3 (organic cation transporter 3), an important drug transporter in the placenta, in the pharmacokinetics and fetal exposure of commonly used therapeutic drugs during pregnancy in normal women and in women infected with the AIDS virus HIV-1. OCT3 belongs to a larger family of drug transporters that handle a variety of drugs and other xenobiotics. Among the members of this gene family, OCT3 is the most relevant to the handling of drugs in women during pregnancy because it is the only OCT subtype that is expressed in the placenta. There have been several interesting and intriguing recent findings regarding the function and expression of OCT3 during pregnancy and its regulation by the HIV-1 protein Tat. These findings for the basis for the following hypotheses: a) OCT3 is expressed on the maternal side of the placental syncytiotrophoblast where it enhances fetal exposure to a wide range of therapeutic drugs; b) The placental expression of OCT3 increases with gestational age and consequently OCT3-dependent pharmacokinetics and fetal exposure of therapeutic drugs and other xenobiotics very significantly at different stages of pregnancy; c) The expression of OCT3 in non-placental tissues is influenced by pregnancy and type 1 sigma receptor and hence the pharmacokinetics of OCT3-specific drugs is significantly altered in women during pregnancy; and d) The expression of OCT3 in placenta and other tissues is down-regulated by HIV-1 Tat and therefore the role of OCT3 in pharmacokinetics and fetal exposure of therapeutic d rugs is altered markedly in women infected with HIV. Studies are proposed in this project to test each of these hypotheses. Studies related to the expression and polarized distribution of OCT3 in the placenta at different gestational ages will be carried out using human placentas. Differential polarization of OCT3 in the placenta versus the kidney and intestine and the influence of progesterone and the type 1 sigma receptor in the regulation of OCT3 expression and function will be investigated using appropriate human cell lines. Substrate specificity studies with emphasis on the therapeutic drugs that are commonly used in women during pregnancy will be done with the cloned human OCT3. The role of OCT3 in the pharmacokinetics and fetal exposure of therapeutic drugs and its modulation of HIV-1 Tat during pregnancy will be assessed using wildtype, OCT3-/- knockout, and Tat-transgenic mice. These studies will generate clinically and therapeutically relevant new information on the role of OCT3 in the handling and fetal exposure of drugs and other xenobiotics in normal women and in women with AIDS.
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