University of Oulu

Henriikka Hakomäki, Hannu Kokki, Marko Lehtonen, Juha Räsänen, Hanna-Marja Voipio, Veli-Pekka Ranta, Merja Kokki, MATERNAL AND FETAL BUPRENORPHINE PHARMACOKINETICS IN PREGNANT SHEEP DURING TRANSDERMAL PATCH DOSING: Buprenorphine pharmacokinetics in pregnant sheep, European Journal of Pharmaceutical Sciences, Volume 165, 2021, 105936, ISSN 0928-0987,

Maternal and fetal buprenorphine pharmacokinetics in pregnant sheep during transdermal patch dosing : buprenorphine pharmacokinetics in pregnant sheep

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Author: Hakomäki, Henriikka1; Kokki, Hannu2; Lehtonen, Marko1;
Organizations: 1School of Pharmacy, University of Eastern Finland, Kuopio, Finland
2School of Medicine, University of Eastern Finland, Kuopio, Finland
3Fetal Medicine Center, Department of Obstetrics and Gynecology, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
4Department of Experimental Surgery, Oulu Laboratory Animal Centre, Oulu University Hospital and University of Oulu, Oulu, Finland
5Department of Anesthesia and Intensive Care, Kuopio University Hospital, Kuopio, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 1.5 MB)
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Language: English
Published: Elsevier, 2021
Publish Date: 2021-09-29


Background: Buprenorphine is used in the opioid maintenance treatment for opioid dependent patients, including pregnant women. Despite the wide use, limited data exists on buprenorphine pharmacokinetics and fetal exposure during pregnancy. The aim of our study was to determine the buprenorphine pharmacokinetics during transdermal patch dosing to pregnant sheep and, to determine the extent of transplacental transfer of buprenorphine to the fetus.

Methods: Pregnant sheep in late gestation (n=50) received 20, 25 or 40 µg/h of buprenorphine as a 7-day extended-release transdermal patch. Plasma samples were collected from the ewe and the fetus on days 1–6, and buprenorphine and norbuprenorphine concentrations were determined. During the exposure period the sheep had a surgical procedure on the second day, a recovery phase, and an experimental procedure on the sixth day. In the experiment, hypoxia was induced under anesthesia for 18 sheep to investigate if decreased fetal pH would cause ion-trapping of buprenorphine in the fetus. The fetal/maternal plasma concentration ratio was determined on the second and on the sixth exposure day at baseline and during hypoxia. Maternal pharmacokinetics were modelled with a population pharmacokinetic method using the data from this study and our previous intravenous administration study.

Results: The transdermal patch provided an extended release of buprenorphine throughout the exposure period, but the release rate declined approximately 20 h after patch placement. The median fetal/maternal plasma concentration ratio was 13–27 % throughout the exposure period at baseline. A ratio over 100 % was observed for four sheep on the sixth exposure day (102–269 %). A minor increase was seen in the median fetal/maternal-ratios during maternal hypoxia. Norbuprenorphine was undetected in all plasma samples.

Conclusions: The low transplacental passage of less than one fourth of the ewe’s exposure supports buprenorphine as an alternative to methadone in opioid maintenance therapy during pregnancy.

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Series: European journal of pharmaceutical sciences
ISSN: 0928-0987
ISSN-E: 1879-0720
ISSN-L: 0928-0987
Volume: 165
Article number: 105936
DOI: 10.1016/j.ejps.2021.105936
Type of Publication: A1 Journal article – refereed
Field of Science: 317 Pharmacy
413 Veterinary science
Funding: This work was supported by the Olvi Foundation, Iisalmi, Finland and The Finnish Concordia Fund, Helsinki, Finland.
Copyright information: © 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (