Background
Bupropion is used for treatment of depression during pregnancy. However, its use as a smoking cessation aid for pregnant women is currently under evaluation.
Objective
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 in vivo. In addition, the concentrations of the drug and its metabolites were determined in the amniotic fluid.
Study Design
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.
Results
The levels of hydroxybupropion and threohydrobupropion in umbilical 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 of threohydrobupropion were higher than those in the corresponding umbilical cord venous plasma.
Conclusion
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 cord venous 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 transfer and recirculation of the amniotic fluid are yet to be determined.
Introduction
A substantial number of women of childbearing age experience clinical depression. Consequently, it is often necessary to start or continue treatment of depression during pregnancy. Bupropion hydrochloride is one of the most frequently prescribed antidepressants in the United States, and is used to treat depression in pregnant women.
Despite the known risks of adverse effects of prenatal smoking on the fetus, 10.7% of pregnant women continue smoking throughout pregnancy. Bupropion, under the brand name Zyban (GlaxoSmithKline, Brentford, United Kingdom), has been successfully used to aid in smoking cession in male and nonpregnant female individuals. However, to date, bupropion has not been approved, by the US Food and Drug Administration, for smoking cessation during pregnancy due to insufficient data on its safety and efficacy.
The exact mechanism of action of bupropion is not well understood. Nevertheless, it appears that bupropion exerts its antidepressant effect by inducing the release of norepinephrine and dopamine, as well as decreasing the reuptake of these 2 neurotransmitters. Moreover, bupropion noncompetitively inhibits several nicotinic acetylcholine receptors, which is thought to contribute to bupropion efficacy as a smoking cessation aid.
The human liver biotransforms bupropion to 3 major metabolites, namely: hydroxybupropion (OHBUP), threohydrobupropion (TB), and erythrohydrobupropion (EB). OHBUP, the major hepatic metabolite of bupropion, is half as potent as the parent drug, while TB and EB have very low activity. At steady state, the plasma level of OHBUP exceeds that of the parent compound by ≥10-fold. Therefore OHBUP is thought to be the major contributor to the pharmacologic activity of bupropion.
Ex vivo studies using dual perfusion of placental lobule demonstrated that bupropion and OHBUP cross the human placenta. Moreover, in vitro experiments showed that bupropion is metabolized by placental tissue, with TB being the major placental metabolite of bupropion. These data, obtained ex vivo and in vitro, suggest that in vivo fetal exposure to bupropion and its pharmacologically active metabolites is plausible. To our knowledge, the extent of maternal/fetal exchange of bupropion and its metabolites in vivo has not been reported.
Amniotic fluid represents another potential pathway of fetal exposure to maternally administered medications. During early gestation, the amniotic fluid consists primarily of ultrafiltrate of maternal serum. However, later in pregnancy, fetal urine contributes significantly to the amniotic fluid content. Amniotic fluid reaches the fetus via several routes, particularly via swallowing into the gastrointestinal tract and possibly via inhalation into the respiratory system. Moreover, prior to fetal skin keratinization, which begins at 19–20 weeks of gestation and is usually complete by 25 weeks of gestation, the amniotic fluid is accessible to the fetus by transcutaneous absorption. If amniotic fluid contains significant quantities of bupropion and its active metabolites, then continuous fetal exposure to the maternally administered drug is plausible.
The primary objective of this work was to examine the extent of in vivo placental passage of bupropion and its major pharmacologically active metabolites. The secondary objective was to determine the concentrations of bupropion and its metabolites in the amniotic fluid.
Materials and Methods
Study overview
The participants in this study were from the cohort of subjects enrolled in the opportunistic study to determine the pharmacokinetics of bupropion during pregnancy. Women with a history or current medical examination consistent with the presence of clinically significant alterations in hepatic, renal, or gastrointestinal function were excluded from participation. The eligible participants in the current investigation were pregnant women taking bupropion within the last 7 days prior to delivery. As an opportunistic study, the subjects were prescribed bupropion previously by their health provider for treatment of depression. The subjects were recruited at the University of Texas Medical Branch, Galveston, TX, and affiliated clinics in Pasadena and Pearland, TX. Written informed consent was obtained prior to data collection. The study was conducted following the protocol approved by the University of Texas Medical Branch Institutional Review Board. Due to the opportunistic design of the study, the obstetrical and neonatal outcomes have not been gathered.
Aliquots of maternal venous blood were obtained and placed in Vacutainer heparinized tubes (Becton Dickinson, Franklin Lakes, NJ) <4 hours prior to delivery or immediately after delivery. The blood was centrifuged for 15 minutes at room temperature, and the supernatant (plasma) transferred to cryogenic vials (Corning Inc., Corning, NY). Aliquots of umbilical cord venous and arterial blood were obtained after the delivery of the placenta and processed as described above. When feasible (and if the collection did not interfere with patient care), amniotic fluid samples were collected as part of the planned cesarean delivery, using a sterile 30-mL needleless syringe after rupture of membranes. All samples were stored at –80°C until analysis of their content.
Quantification of bupropion, OHBUP, and TB
The concentrations of bupropion, OHBUP and TB in maternal plasma, umbilical cord venous and arterial plasma, and amniotic fluid were determined by liquid chromatography-mass spectrometry according to a method developed, validated, and reported by our laboratory. The lower limits of quantification (LLOQ) and limits of detection (LOD) for a sample of 200 μL of amniotic fluid and plasma were as follows: bupropion, 0.125 and 0.0625 ng/mL, OHBUP, 0.5 and 0.2 ng/mL, and TB, 0.3 and 0.12 ng/mL.
Data analysis
The concentrations of bupropion and its metabolites in plasma and amniotic fluid below their respective LLOQ were deemed undetectable. The extent of placental passage of the drug or its metabolites was expressed/calculated as the ratio of the analyte concentration in the umbilical cord venous plasma to maternal plasma. Pairs with undetectable maternal or fetal concentrations of bupropion, OHBUP, and TB were excluded from their respective placental passage analysis. Data are presented as median and interquartile range (IQR), and mean ± SD when specified.
Materials and Methods
Study overview
The participants in this study were from the cohort of subjects enrolled in the opportunistic study to determine the pharmacokinetics of bupropion during pregnancy. Women with a history or current medical examination consistent with the presence of clinically significant alterations in hepatic, renal, or gastrointestinal function were excluded from participation. The eligible participants in the current investigation were pregnant women taking bupropion within the last 7 days prior to delivery. As an opportunistic study, the subjects were prescribed bupropion previously by their health provider for treatment of depression. The subjects were recruited at the University of Texas Medical Branch, Galveston, TX, and affiliated clinics in Pasadena and Pearland, TX. Written informed consent was obtained prior to data collection. The study was conducted following the protocol approved by the University of Texas Medical Branch Institutional Review Board. Due to the opportunistic design of the study, the obstetrical and neonatal outcomes have not been gathered.
Aliquots of maternal venous blood were obtained and placed in Vacutainer heparinized tubes (Becton Dickinson, Franklin Lakes, NJ) <4 hours prior to delivery or immediately after delivery. The blood was centrifuged for 15 minutes at room temperature, and the supernatant (plasma) transferred to cryogenic vials (Corning Inc., Corning, NY). Aliquots of umbilical cord venous and arterial blood were obtained after the delivery of the placenta and processed as described above. When feasible (and if the collection did not interfere with patient care), amniotic fluid samples were collected as part of the planned cesarean delivery, using a sterile 30-mL needleless syringe after rupture of membranes. All samples were stored at –80°C until analysis of their content.
Quantification of bupropion, OHBUP, and TB
The concentrations of bupropion, OHBUP and TB in maternal plasma, umbilical cord venous and arterial plasma, and amniotic fluid were determined by liquid chromatography-mass spectrometry according to a method developed, validated, and reported by our laboratory. The lower limits of quantification (LLOQ) and limits of detection (LOD) for a sample of 200 μL of amniotic fluid and plasma were as follows: bupropion, 0.125 and 0.0625 ng/mL, OHBUP, 0.5 and 0.2 ng/mL, and TB, 0.3 and 0.12 ng/mL.
Data analysis
The concentrations of bupropion and its metabolites in plasma and amniotic fluid below their respective LLOQ were deemed undetectable. The extent of placental passage of the drug or its metabolites was expressed/calculated as the ratio of the analyte concentration in the umbilical cord venous plasma to maternal plasma. Pairs with undetectable maternal or fetal concentrations of bupropion, OHBUP, and TB were excluded from their respective placental passage analysis. Data are presented as median and interquartile range (IQR), and mean ± SD when specified.
Results
In all, 22 pregnant subjects participated in the study, which included 16 white/non-Hispanic, 5 white/Hispanic, and 1 black/non-Hispanic subjects ( Table 1 ). The subjects were receiving the following bupropion therapy: 150 mg twice a day (n = 8), 300 mg daily (n = 3), 75 mg twice a day (n = 3), 150 mg daily (n = 6), 100 mg daily (n = 1), and 75 mg daily (n = 1) ( Table 1 ). The time of the last dose was not available for 8 subjects ( Table 1 ). The average age for the participating women was 29.5 ± 6.6 years, and average gestational age at delivery was 38 ± 1 weeks. For maternal blood (n = 22), the corresponding umbilical cord venous (n = 22) and arterial (n = 17) blood samples were collected. Amniotic fluid samples were obtained from 9 deliveries.
| Patient | Age, y | Race/ethnicity | GA, wk d | Bupropion dose, | Time between last dose and delivery, h | Umbilical cord venous plasma, ng/mL | Maternal venous plasma, ng/mL | Umbilical cord venous plasma to maternal plasma ratio | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| mg | Frequency | BUP | OHBUP | TB | BUP | OHBUP | TB | BUP (n = 18) | OHBUP, n = 18 | TB, n = 21 | |||||
| A | 32 | White/non-Hispanic | 37 4 | 150 | BID | 12 | 4.5 | 204.6 | 168.3 | 8.0 | 497.2 | 289.9 | 0.56 | 0.41 | 0.58 |
| B | 23 | White/non-Hispanic | 37 1 | 150 | BID | 16 | <LOD | <LLOQ | 3.1 | 0.13 | 1.4 | 4.4 | ND | ND | 0.70 |
| C | 33 | White/Hispanic | 39 | 150 | BID | NA | <LOD | <LLOQ | 6.4 | 0.22 | 1.5 | 9.8 | ND | ND | 0.65 |
| D | 38 | White/non-Hispanic | 36 6 | 150 | BID | 10 | 15.9 | 205.8 | 111.9 | 29.0 | 687.4 | 190.9 | 0.55 | 0.30 | 0.59 |
| E | 38 | White/non-Hispanic | 39 0 | 150 | BID | 29 | 2.5 | 125.5 | 45.0 | 5.9 | 565.6 | 77.0 | 0.42 | 0.22 | 0.59 |
| F | 25 | White/non-Hispanic | 39 1 | 150 | BID | NA | <LOD | <LOD | <LOD | <LOD | <LOD | <LLOQ | ND | ND | ND |
| G | 30 | White/Hispanic | 38 2 | 150 | BID | NA | 0.24 | 0.83 | 6.6 | 0.4 | 4.4 | 10.4 | 0.53 | 0.19 | 0.63 |
| H | 30 | Black/non-Hispanic | 34 5 | 150 | BID | 2 | 2.2 | 17.4 | 59.6 | 5.4 | 138.1 | 125.8 | 0.41 | 0.13 | 0.47 |
| I | 42 | White/non-Hispanic | 37 5 | 300 | QD | 21 | 12.2 | 103.1 | 88.6 | 26.5 | 912.4 | 198.8 | 0.46 | 0.11 | 0.45 |
| J | 24 | White/non-Hispanic | 37 3 | 300 | QD | NA | 20.4 | 150.5 | 198.0 | 36.4 | 716.6 | 323.8 | 0.56 | 0.21 | 0.61 |
| K | 25 | White/non-Hispanic | 40 1 | 300 | QD | NA | 6.2 | 249.1 | 244.5 | 1.8 | 780.7 | 359.5 | 3.48 | 0.32 | 0.68 |
| L | 42 | White/Hispanic | 38 2 | 75 | BID | 25 | 0.91 | 44.7 | 18.6 | 1.8 | 172.5 | 28.7 | 0.50 | 0.26 | 0.65 |
| M | 31 | White/Hispanic | 36 5 | 75 | BID | 45 | 6.1 | 108.9 | 219.5 | 1.2 | 536.7 | 360.6 | 4.94 | 0.20 | 0.61 |
| N | 29 | White/non-Hispanic | 37 4 | 75 | BID | NA | 18.1 | 84.3 | 58.7 | 4.7 | 542.5 | 124.9 | 3.86 | 0.16 | 0.47 |
| O | 24 | White/non-Hispanic | 39 2 | 150 | QD | 20 | 2.9 | 32.9 | 24.0 | 9.7 | 279.6 | 58.9 | 0.30 | 0.12 | 0.41 |
| P | 21 | White/non-Hispanic | 39 0 | 150 | QD | 48 | 0.7 | 2.3 | 21.1 | 1.9 | 11.8 | 39.4 | 0.36 | 0.20 | 0.54 |
| Q | 25 | White/non-Hispanic | 39 0 | 150 | QD | 48 | 14.3 | 282.6 | 239.7 | 28.6 | 1180.9 | 378.2 | 0.50 | 0.24 | 0.63 |
| R | 28 | White/non-Hispanic | 39 0 | 150 | QD | 4 | 28.5 | 104.2 | 66.2 | 53.7 | 366.7 | 90.4 | 0.53 | 0.28 | 0.73 |
| S | 39 | White/non-Hispanic | 39 4 | 150 | QD | 30 | 3.8 | 115.2 | 90.7 | 4.4 | 362.3 | 143.9 | 0.86 | 0.32 | 0.63 |
| T | 22 | White/Hispanic | 37 0 | 150 | QD | NA | 0.22 | 0.70 | 12.4 | 0.68 | 9.7 | 29.6 | 0.33 | 0.07 | 0.42 |
| U | 25 | White/Hispanic | 41 2 | 100 | QD | NA | <LOD | <LOD | 0.4 | <LOD | <LLOQ | 0.5 | ND | ND | 0.80 |
| V | 23 | White/non-Hispanic | 38 2 | 75 | QD | 43 | 6.8 | 84.3 | 72.8 | 5.3 | 482.7 | 97.3 | 1.29 | 0.17 | 0.75 |
| Median | 28.5 | 38 4 | 5.3 | 103.6 | 59.6 | 5.0 | 424.7 | 97.3 | 0.53 | 0.21 | 0.61 | ||||
| IQR | 42 | 41 2 | 11.5 | 108.3 | 93.3 | 12.3 | 489.5 | 169.2 | 0.35 | 0.12 | 0.11 | ||||
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