Pregnancy Alters CYP and UGT Mediated Metabolism of Buprenorphine.

Publication date: Jan 09, 2020

In the United States, drug addiction has become a nationwide health crisis. Recently, buprenorphine (BUP), a maintenance therapy approved by the FDA, has been increasingly used in pregnant women for the treatment of opioid use disorder. Pregnancy is associated with various anatomic and physiological changes, which may result in altered drug pharmacokinetics. Previously, we reported that dose-adjusted plasma concentrations of BUP are lower during pregnancy than post-pregnancy. The mechanism responsible for this difference has not yet been defined. Our study aimed to evaluate alterations in cytochromes P450 (CYP)- and uridine diphosphate glucunosyltransferases (UGT)- mediated metabolism of BUP during pregnancy to determine the mechanism(s) responsible for this observation.

Data from two clinical studies were included in the current analysis. Study 1 was a prospective, open-labeled, non-randomized longitudinal BUP pharmacokinetic (PK) study in pregnant women with a singleton gestation, stabilized on twice-daily sublingual BUP opioid substitution therapy. Each subject participated in up to three studies during and after pregnancy (the 2, 3 trimester, and postpartum). The design of study 2 was similar to study 1, with patients evaluated at different time points during the pregnancy (1, 2 – half of pregnancy), as well as during the postpartum period. Additionally, the dosing frequency of BUP study 2 participants was not restricted to twice-daily dosing. At each study visit, blood samples were collected prior to a BUP dose, followed by multiple collection times (10-12) after the dose, for up to 12 h or till the end of the dosing interval. Plasma concentrations of BUP and three metabolites were quantified using validated ultra-performance liquid chromatography-tandem mass spectrometric assays.

In total, 19, 18 and 14 subjects completed the PK study during 1 / 2 trimester, 3 trimester, and postpartum, respectively. The AUC ratios of norbuprenorphine and norbuprenorphine glucuronide to buprenorphine, a measure of CYP3A mediated N-demethylation, were 1.89, 1.84, and 1.33 during the 1 and 2, 3 trimesters, and postpartum, respectively. The AUC ratios of buprenorphine glucuronide to BUP, indicative of UGT activity, were 0.71, 2.07, and 0.3 at 1 / 2 trimesters, 3 trimester, and postpartum, respectively. Linear mixed effect modeling analysis indicated that the AUC ratios of CYP- and UGT- mediated metabolism of BUP were significantly higher during pregnancy compared to postpartum.

The CYP- and UGT- activities were significantly increased as determined by the metabolic ratios of BUP during pregnancy compared to the postpartum period. The increased UGT activity appeared to account for a substantial part of the observed change in metabolic activity during pregnancy. This is in agreement with the need for BUP dose increment in pregnant women to reach similar BUP exposure and therapeutic effect as in non-pregnant subjects.

Zhang, H., D, Bastian Pharm., Zhao, W., Chen, H., Caritis, S.N., , Shaik, Chaphekar, N., and Venkataramanan, R. Pregnancy Alters CYP and UGT Mediated Metabolism of Buprenorphine. 04499. 2020 Ther Drug Monit.

Concepts Keywords
AUC Opioids
Blood Drugs
Buprenorphine RTT
Cytochromes P450 Midwifery
Demethylation Women’s health
Drug Addiction Ethers
FDA Phenols
Frequency Pregnancy
Gestation Buprenorphine
Glucuronide Childbirth
Indicative Norbuprenorphine
Liquid Chromatography Postpartum period
Mass Spectrometric Drug Metabolism
Metabolism
Opioid
Pharmacokinetic
Pharmacokinetics
Plasma
Postpartum
Postpartum Period
Pregnancy
Singleton
Sublingual
Substitution Therapy
Tandem
UGT
United States
Uridine Diphosphate

Semantics

Type Source Name
pathway REACTOME Metabolism
drug DRUGBANK Buprenorphine
disease MESH drug addiction
drug DRUGBANK Uridine
disease MESH multiple

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