The goal of this investigation is to provide the information needed to determine the potential of bupropion for pharmacotherapy of the pregnant smoker. The efficacy of bupropion for smoking cessation in adult males and non- pregnant females has been demonstrated. However, the use of bupropion for treatment of the pregnant smokers requires additional data on its bio-disposition during pregnancy and its potential risk to fetal development. Currently, information on the effects of bupropion on the pregnant woman and the developing fetus is scarce and consequently precludes its consideration for clinical trials in this patient population. Therefore, the focus of this application is to provide information on the bio-disposition of bupropion and its major pharmacologically active metabolite hydroxybupropion by human placenta and to determine their concentrations in the fetal circulation. The following specific aims will be investigated: 1. Transplacental transfer and distribution of bupropion and hydroxybupropion across human placenta and their effects on selected placental functions; 2. Identification of the major placental enzyme(s) responsible for the metabolism of bupropion; 3. The role of placental efflux transporters P-gp and BCRP in determining the concentration of bupropion and hydroxybupropion in the fetal circulation; 4. The effect of pregnancy on the activity of the hepatic enzyme CYP2B6 which metabolizes bupropion utilizing the baboon as an animal model. Data providing the above information will be obtained by utilizing ex vivo, in vitro, and in vivo model systems of dual perfusion of human placental lobule, placental microsomal preparations, and the pregnant baboon as a nonhuman primate. The P.I. has over 8 years of experience in utilizing the technique of dual perfusion of placental lobule, investigating placental metabolism and the role placental efflux transporters. ? ? ?
