Role of transporter-mediated efflux in the placental biodisposition of bupropion and its metabolite, OH-bupropion

Abstract

Cigarette smoking during pregnancy is a preventable risk factor associated with maternal and fetal complications. Bupropion is an antidepressant used successfully for smoking cessation in non-pregnant patients. Our goal is to determine whether it could benefit the pregnant patient seeking smoking cessation. The aim of this investigation was to determine the role of human placenta in the disposition of bupropion and its major hepatic metabolite, OH-bupropion. The expression of efflux transporters P-gp and BCRP was determined in placental brush border membrane (n  = 200) and revealed a positive correlation (p  < 0.05). Bupropion was transported by BCRP (K _t 3 μM, V _max 30 pmol/mg protein/min) and P-gp (K _t 0.5 μM, V _max 6 pmol/mg protein*min) in placental inside-out vesicles (IOVs). OH-bupropion crossed the dually-perfused human placental lobule without undergoing further metabolism, nor was it an efflux substrate of P-gp or BCRP. In conclusion, our data indicate that human placenta actively regulates the disposition of bupropion (via metabolism, active transport), but not its major hepatic metabolite, OH-bupropion.

Introduction

Cigarette smoking during pregnancy has been associated with spontaneous abortion, placental pathology, preterm labor, low birth weight, stillbirth, sudden infant death syndrome, and childhood developmental problems [1]. Approximately 13% of mothers report smoking during the last 3 months of pregnancy [2], and many find it hard to stop or reduce smoking without the aid of medication. The benefits of smoking cessation during pregnancy include significant increase in birth weight and reduction in risk of preterm birth, as well as long-term health benefits to both mother and child [3].

Currently, there is no approved medical therapy for smoking cessation during pregnancy. Occasionally health care providers recommend the use of nicotine replacement therapy (NRT) for those pregnant women who desire to quit smoking and fail other non-pharmacotherapeutic interventions. However, maternal exposure to nicotine has also been associated with risk to the developing fetus and newborn. Prenatal exposure to nicotine in animals was associated with blunted newborn respiratory response and increased rate of death [4]; anxiety, hyperactivity, and cognitive impairment in offspring [5]; and vasoconstriction related to decreased uteroplacental blood flow [6]. In humans, congenital malformations were higher among women who used NRT (patch, gum, or inhaler) during the first trimester than with nonsmokers [7]. Due to concern over safety of the developing fetus exposed to NRT, the goal of investigations in our laboratory is to evaluate an alternative to NRT for smoking cessation during pregnancy.

Bupropion is an antidepressant used successfully for smoking cessation in non-pregnant patients [8]. Accordingly, bupropion may also offer therapeutic benefit for smoking cessation in pregnant patients. However, its safety as a medication to be used during pregnancy remains unclear. Bupropion is labeled as Category C by the US Food and Drug Administration (i.e., data from animal models revealed adverse effects and there are not adequate studies in humans), but potential benefits may warrant its use during pregnancy despite potential risks [9].

Preclinical investigations in our laboratory on the biodisposition of bupropion by human placenta revealed that it crosses from the maternal-to-fetal circulation [10], and that it is metabolized by placental tissue [11]. Placental transfer of bupropion from the maternal-to-fetal circulation was approximately 20% [10]. This is less than the 30–40% reported transfer of nicotine which diffuses freely across the placental tissue [12], [13], [14]. The lower placental transfer of bupropion could be explained, in part, by the activity of placental efflux transporters. We have demonstrated that efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) have an active role in the efflux of their substrates across placental apical membrane [15]. Bupropion may be a P-gp substrate, as suggested by its stimulation of ATP hydrolysis by P-gp expressing membranes [16]. However, a direct determination of its transport by P-gp and/or other transporters expressed in placental apical membrane has not been reported to date.

An earlier report from our laboratory provided evidence that bupropion is metabolized by placental tissue during its perfusion [11]. The major metabolites of bupropion (threo- and erythro-hydrobupropion) formed by the placental tissue were distinct from the major hepatic metabolite (OH-bupropion), suggesting the placenta has a unique role in regulating the metabolic fate of bupropion. However, since bupropion is extensively metabolized to OH-bupropion, with plasma metabolite levels exceeding those of the parent compound [17], this active metabolite will be present in the circulation of pregnant patients receiving bupropion for treatment. Thus, concern over potential fetal exposure to OH-bupropion should be taken into consideration and the role of the placenta in its biodisposition warrants further investigation.

Taken together, the goals of this investigation were to determine the role of the placenta in the active regulation (metabolism, efflux transport) of OH-bupropion disposition compared to its parent compound, bupropion. Information obtained will be necessary for evaluating the extent of fetal exposure to bupropion and OH-bupropion, and consequently the safety of bupropion as an alternative medication for smoking cessation therapy in pregnant patients.