Maternally administered naltrexone and its major active metabolite 6β-naltrexol transport across the placental barrier in vitro

Abstract

Opioid use disorder (OUD) has become a growing concern in the U.S. and has been a dominant presence among pregnant women, resulting in an unprecedented amount of prescription medications, particularly naltrexone (NTX), prescribed for pregnant women. Because of unknown potential harm that NTX can impose on the fetus and its premature brain, the needs for safety and regulation of NTX are still undetermined. To address this issue, a microfluidic device is fabricated to mimic structural phenotypes and physiological characteristic of an in vivo placental barrier to evaluate near-transport simulations of NTX and its primary metabolite, 6{beta}-naltrexol, across the placental barrier. Following transport analysis, cell layers are evaluated for possible gene-expressions released by an in vivo human placenta during NTX and 6{beta}-naltrexol placental exposure. When a 100 ng/mL dose of NTX and 6{beta}-naltrexol (1:1) is administered to the maternal channel, the mean fetal concentration for co-culture models exhibited ~2.5 % of NTX and ~2.2% of 6{beta}-naltrexol of the initial maternal concentration. To prototype and simulate fetal-brain exposure, perfusate from a fetal channel is directed to cultured N27 cells that are then evaluated for gene-expression.