Urinary excretion of buprenorphine, norbuprenorphine, buprenorphine-glucuronide, and norbuprenorphine-glucuronide in pregnant women receiving buprenorphine maintenance treatment

Abstract

Background: Buprenorphine (BUP) is under investigation as a medication therapy for opioid-dependent pregnant women. We investigated BUP and metabolite disposition in urine from women maintained on BUP during the second and third trimesters of pregnancy and postpartum.

Methods: We measured BUP, norbuprenorphine (NBUP), buprenorphine glucuronide (BUP-Gluc), and NBUP-Gluc concentrations in 515 urine specimens collected thrice weekly from 9 women during pregnancy and postpartum. Specimens were analyzed using a fully validated liquid chromatography-mass spectrometry method with limits of quantification of 5 microg/L for BUP and BUP-Gluc and 25 microg/L for NBUP and its conjugated metabolite. We examined ratios of metabolites across trimesters and postpartum to identify possible changes in metabolism during pregnancy.

Results: NBUP-Gluc was the primary metabolite identified in urine and exceeded BUP-Gluc concentrations in 99% of specimens. Whereas BUP-Gluc was identified in more specimens than NBUP, NBUP exceeded BUP-Gluc concentrations in 77.9% of specimens that contained both analytes. Among all participants, the mean BUP-Gluc:NBUP-Gluc ratio was significantly higher in the second trimester compared to the third trimester, and there were significant intrasubject differences between trimesters in 71% of participants. In 3 women, the percent daily dose excreted was higher during pregnancy than postpregnancy, consistent with other data indicating increased renal elimination of drugs during pregnancy.

Conclusions: These data are the first to evaluate urinary disposition of BUP and metabolites in a cohort of pregnant women. Variable BUP excretion during pregnancy may indicate metabolic changes requiring dose adjustment during later stages of gestation.

Fig. 1

Disetribution of BUP, NBUP, BUP-Gluc, and NBUP-Gluc in 667 urine specimens collected from 9 women during pregnancy.

Fig. 2

(A), Mean (SD) BUP-Gluc and NBUP-Gluc creatinine-corrected concentrations. (B), Mean (SD) NBUP and NBUP-Gluc concentrations and ratios (insets) in urine specimens from all participants containing both analytes during the second and third trimesters and postpartum.

Fig. 3

Cumulative excretion of NBUP, BUP-Gluc, NBUP-Gluc, and total metabolites for participant B (panel A), participant D (panel B), and participant H (panel C) over 24 h at various time points in pregnancy.