Bupropion therapy during pregnancy: the drug and its major metabolites in umbilical cord plasma and amniotic fluid

Abstract

Bupropion is used for treatment of depression during pregnancy. However, its use as a smoking cessation aid for pregnant women is currently under evaluation. The aim of this opportunistic study was to investigate the transfer of bupropion and its major pharmacologically active metabolites, hydroxybupropion and threohydrobupropion, across the placenta invivo. Inaddition, the concentrations of the drug and its metabolites were determined in the amniotic fluid. The following samples were collected at deliveries from 22 women taking bupropion: maternal blood (n= 22), umbilical cord venous blood (n= 22), and amniotic fluid (n= 9). The concentrations of the drug and its metabolites in blood plasma and amniotic fluid were determined by means of liquid chromatography-mass spectrometry. Placental passage was calculated as a ratio of umbilical cord venous plasma to maternal plasma concentrations. The levels of hydroxybupropion and threohydrobupropion inumbilical cord venous plasma were invariably lower than their corresponding concentrations in maternal plasma. The concentrations of bupropion in umbilical cord plasma were lower than in maternal plasma in the majority of the maternal-cord blood pairs. The median values of the umbilical cord venous plasma to maternal plasma ratios were: bupropion, 0.53 (interquartile range 0.35, n= 18), hydroxybupropion, 0.21 (interquartile range 0.12, n= 18), and threohydrobupropion, 0.61 (interquartile range 0.11, n= 21). In umbilical cord venous plasma, the median concentration of bupropion was 5.3 ng/mL; hydroxybupropion, 103.6 ng/mL; and threohydrobupropion, 59.6 ng/mL. Bupropion and its metabolites were detectable in the amniotic fluid but the concentrations ofthreohydrobupropion were higher than those in the corresponding umbilical cord venous plasma. Bupropion and its active metabolites cross the placenta to the fetal circulation. The concentrations of hydroxybupropion and threohydrobupropion in umbilical cord venous plasma were higher than bupropion concentrations suggesting a higher fetal exposure to the metabolites than the parent drug. The higher levels of threohydrobupropion in the amniotic fluid than those in umbilical cordvenous plasma suggest that enzymes involved in the metabolism of bupropion to threohydrobupropion are most likely active in the fetus.The biological consequences of fetal exposure to maternally administered bupropion and/or its active metabolites via placental transferand recirculation of the amniotic fluid are yet to be determined.