BUP and metabolite pharmacokinetics after high dose (14–20 mg) SL BUP tablet administration were evaluated at different stages of gestation and postpartum in a small group of opioid-dependent pregnant women. Plasma, OF and sweat specimens were collected for 24 h in 3 different pharmacokinetic sessions at gestation weeks 28 or 29 and 34, and 2 months after delivery. The objectives were to evaluate if BUP pharmacokinetics were altered across pregnancy, and to compare BUP and metabolite disposition in three matrices, plasma, oral fluid and sweat.
Several plasma BUP pharmacokinetic studies were published after high-dose SL BUP tablet administration to adult male and non-pregnant female, experienced7–9, 12
opioid users. BUP plasma Tmax1
in the present study, 1.6±0.8 h, agreed with those noted in previous studies, 0.75 to 1.2 h9, 12, 13
. Dose-adjusted BUP Cmax1
in these other studies was 0.19–0.65 ng/mL/mg, and dose-adjusted AUC BUP was 1.9–4.4 h*ng/mL/mg7–9, 12, 13
. Dose-adjusted BUP Cmax1
in the present study during gestation and postpartum were different; values were lower for gestational weeks 28–29 (0.1–0.3ng/mL/mg, 1.1–2.0 h*ng/mL/mg) and 34 (0.1–0.2 ng/mL/mg, 0.1–1.7 h*ng/mL/mg), as compared to 2 months after delivery (0.2–2 ng/mL per mg, 1.4–14.1 h*ng/mL per mg).
Plasma NBUP pharmacokinetic parameters (Tmax
and AUC) were reported in just one previous study by Harris et al.8
. After 16 mg SL BUP (n=8), mean plasma NBUP Tmax
was 1.44±0.86 h, Cmax
2.54±1.29 ng/mL and AUC 32.64±7.63 h*ng/mL8
. In the present study, after 14–20 mg dose, NBUP Tmax1
was similar at 28 or 29 and 34 gestation week and 2 months after delivery (1.6±0.7 h), while Cmax1
values were lower for gestational weeks 28–29 (1.8–5.7ng/mL/mg, 18.8–83.0 h*ng/mL/mg) and 34 (0.8–5.5 ng/mL/mg, 7.2–92.9 h*ng/mL/mg), as compared to 2 months after delivery (3.4–27.5 ng/mL per mg, 32.5–397.8 h*ng/mL per mg), as occurred for BUP.
The observed variations in BUP and NBUP pharmacokinetic parameters could be explained by the physiologic changes that occur throughout pregnancy. Cmax
for BUP and NBUP tended to be lower in pregnancy, especially at the 34th
gestational week. It is well known that the apparent volume of distribution (Vd) increases throughout pregnancy20
; and therefore, these Vd changes may decrease Cmax
. BUP AUC0–24h
also tended to decrease during pregnancy, most likely because CYP3A4 and UGT activity, such as UGT2B7, is increased in this period20, 32, 33
, accelerating BUP elimination. These UGT activity changes also may reduce NBUP AUC0–24h
. BUP and NBUP Cmax
changes in participant B who delivered monozygotic twins, were much higher after delivery than for participants A and C who had single births.
To our knowledge, these are the first published plasma BUP- and NBUP-Gluc pharmacokinetic data. We found no consistent BUP and NBUP-Gluc Cmax
changes in pregnancy compared to postpartum. BUP metabolite plasma levels could be decreased in pregnancy due to increased glomerular filtration rate (GFR) compared to postpartum levels25
. Kacinko et al.34
examined 24-h BUP and metabolite urinary excretion in the same 3 participants. In all participants, cumulative BUP metabolite excretion, mainly NBUP-Gluc, was higher in sessions before birth compared to postpartum. BUP metabolite levels also could be higher during pregnancy due to increased BUP metabolism20, 32, 33
. Inter-individual variations were noted, requiring further study of these possible-contributing factors.
All participants showed a secondary peak for BUP and metabolites about 8 h after dosing, except NBUP-Gluc in participant A 2.5 months after delivery. McAleer et al.13
also reported a secondary peak for BUP 10 h post-dose after 16 mg SL BUP. Cone et al.35
suggested a BUP depot effect in the oral mucosa following SL administration. Thus, BUP may be released from this oral depot and produce a secondary peak for BUP and metabolites. As reported by others8, 13
, fluctuating terminal BUP plasma concentrations, possibly due to enterohepatic recirculation, also were observed in the present study.
BUP concentrations were much higher in OF than plasma due to oral contamination from SL administration and the oral mucosal BUP depot35
. A statistically significant but weak correlation was noted for BUP plasma and OF concentrations, and between BUP/NBUP plasma and OF ratios. The low coefficient of correlation (r=0.2) was most likely due to OF contamination from SL BUP and/or the contribution from the oral mucosal BUP depot. BUP and NBUP OF/plasma ratios decreased with time of collection post-dose; however, high inter-individual variations were observed (, ). These results suggest that it is not possible to predict plasma concentrations from OF levels. As expected, BUP-Gluc and NBUP-Gluc were not detected in most OF specimens at the method’s LOQs 0.1 ng/mL for BUP-Gluc and 0.5 ng/mL for NBUP-Gluc. Drug and metabolite incorporation into OF occurs mainly by passive diffusion from blood, with the extent of transfer dependent on the drug's physicochemical properties (polarity, molecular weight and protein binding). BUP- and NBUP-Gluc transfer into OF is expected to be low due to their high polarity and molecular weight >500 Da.
BUP and NBUP were detected in just 4 sweat specimens and in low concentrations. Concheiro et al.31
reported BUP and NBUP concentrations up to 2.3 and up to 1 ng/patch, respectively, in sweat patches worn for 7 days from a BUP-maintained opioid-dependent woman receiving 15.6 mg/day. Kintz et al36
reported BUP concentrations of 1.3–153.2 ng/patch and NBUP in just one case at 3.1 ng/patch, in sweat patches worn for 5 days by 16 participants receiving 0.4–6 mg BUP/day. A sweat patch wear period of less than 24 h is insufficient to sensitively detect BUP exposure. BUP is a highly potent opioid and doses are low, even during daily opioid-dependence treatment.
This study had several limitations. This was an additional component of a clinical trial that compared methadone and BUP treatment in opioid-dependent pregnant women28
; the study is underpowered as only 3 subjects entered the pharmacokinetic component. However, the data are unique in assessing pharmacokinetic data at two different gestational weeks and postpartum in the same women, and in plasma, oral fluid and sweat. These preliminary data suggest that BUP and metabolite pharmacokinetics are modified during pregnancy.
BUP and metabolites Tmax
were not affected by pregnancy; however, BUP and NBUP Cmax
tended to be lower during pregnancy compared to postpartum levels. These data suggest that, like methadone, pregnant opioid-dependent women may require increased BUP dose during gestation and decreased dose postpartum. Yet, across all patients in the primary study, participants did not report nor were they observed to have symptoms or signs of over- or under-medication resulting in BUP dose changes up to 4 weeks post-partum37
. Thus, additional research is needed to confirm these preliminary results. The disposition of BUP and metabolites in alternative matrices, OF and sweat, were studied in order to determine their utility in monitoring BUP exposure, and to improve interpretation of results as compared to plasma. OF was useful to monitor BUP exposure, although BUP and NBUP plasma concentrations could not be deduced from OF concentrations due to high variability in concentrations. Sweat patch testing showed that a collection period of greater than 24 h was necessary to identify BUP exposure.