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 (Kt 3 μM, Vmax 30pmol/mg protein/min) and P-gp (Kt 0.5 μM, Vmax 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.

Metabolism and Disposition of Bupropion in Pregnant Baboons (Papio cynocephalus)

“…The neonatal/maternal ratios of BUP and OH-BUP after 1 hour of BUP injection were 0.89 6 18 and 0.24 6 0.10, respectively. Previously, we reported the transfer of BUP and OH-BUP across the dually perfused human placental lobule (Earhart et al, 2010;Hemauer et al, 2010). After 1 hour of BUP perfusion, the concentration of BUP in the fetal circuit in vitro was 24 6 3% of its initial concentration in the maternal circuit and the fetal-to-maternal ratio was 0.68 6 0.15, which agrees with the data obtained in this investigation.…”

Pharmacotherapy for Mood Disorders in Pregnancy

“…During pregnancy, the placenta is a site of bupropion biotrans-formation, although carbonyl reduction is favored over oxidative biotransformation at this tissue site. 38,85,86 To a lesser extent, the CYP1A2, 2A6, 2C9, 2D6, 2E1, and 3A4 isoforms are also involved in bupropion metabolism. 87–89 Sex hormones inhibit up to 50% of bupropion hydroxylation via CYP2B6, 28 but the isoform shows high interindividual variability.…”

Placental control of drug delivery

“…Cortisol, a well-known endogenous glucocorticoid, was shown to be effluxed by P-gp in a choriocarcinoma cell line [81]. P-gp is also known to prevent placental passage of dexamethasone, a synthetic glucocorticoid, as well as a number of other drugs including verapamil, paclitaxel, bupropion, zidovudine, tenofovir disoproxil fumarate, cyclosporine, and others [50,52,61,80–82]. P-gp is often inhibited in a competitive manner using many of these same substrates to test whether compounds are substrates of P-gp in certain models.…”

“…An interesting modulator of BCRP expression is hypoxia [86]. Drugs that are known substrates of BCRP include zidovudine, tenofovir disoproxil fumarate, bupropion, nitrofurantoin, and glyburide, to name a few [52,80,82,87,88]. Many of the substrates of BCRP are also substrates of P-gp, demonstrating redundancy in placental efflux capacity.…”