Hakomäki, H., Eskola, S., Kokki, H., Lehtonen, M., Räsänen, J., Laaksonen, S., Voipio, H.-M., Ranta, V.-P., & Kokki, M. (2022). Central nervous system distribution of buprenorphine in pregnant sheep, fetuses and newborn lambs after continuous transdermal and single subcutaneous extended-release dosing. European Journal of Pharmaceutical Sciences, 178, 106283. https://doi.org/10.1016/j.ejps.2022.106283
Central nervous system distribution of buprenorphine in pregnant sheep, fetuses and newborn lambs after continuous transdermal and single subcutaneous extended-release dosing
|Author:||Hakomäki, Henriikka1; Eskola, Sophia1; Kokki, Hannu2;|
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 Comparative Medicine, Oulu Laboratory Animal Centre, Oulu University Hospital and University of Oulu, Oulu, Finland
5Department of Anesthesiology and Intensive Care, Kuopio University Hospital, Kuopio, Finland
|Online Access:||PDF Full Text (PDF, 1 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2022122974050
|Publish Date:|| 2022-12-29
Buprenorphine is used during pregnancy for the treatment of opioid use disorder. Limited data exist on the central nervous system (CNS) permeation and distribution, and on the fetal exposure to buprenorphine. The aim of our study was to determine the extent of buprenorphine distribution to CNS in the pregnant sheep, and their fetus at steady-state, and their newborn lambs postdelivery, using three different dosing regimens. Twenty-eight pregnant ewes in late gestation received buprenorphine via 7-day transdermal patch releasing buprenorphine 20 µg/h (n=9) or 40 µg/h (n=11), or an extended-release 8 mg/week subcutaneous injection (n=8). Plasma, cerebrospinal fluid, and CNS tissue samples were collected at steady-state from ewes and fetuses, and from lambs 0.33–45 hours after delivery. High accumulation of buprenorphine was observed in all CNS tissues. The median CNS/plasma concentration -ratios of buprenorphine in different CNS areas ranged between 13 and 50 in the ewes, and between 26 and 198 in the fetuses. In the ewes the CNS/plasma -ratios were similar after the three dosing regimens, but higher in the fetuses in the 40 µg/h dosing group, medians 65–122, than in the 20 µg/h group, medians 26–54. The subcutaneous injection (theoretical release rate 47.6 µg/h) produced higher concentrations than observed after 40 µg/h transdermal patch dosing. The median fetal/maternal concentration -ratios in different dosing groups ranged between 0.21 and 0.54 in plasma, and between 0.38 and 1.3 in CNS tissues, respectively, with the highest ratios observed in the spinal cord. Buprenorphine concentrations in the cerebrospinal fluid were 8–13 % of the concurrent plasma concentration in the ewes and 28 % in the fetuses. Buprenorphine was quantifiable in the newborn lambs’ plasma and CNS tissues two days postdelivery. Norbuprenorphine was analyzed from all plasma, cerebrospinal fluid, and CNS tissue samples but was nondetectable or below the LLOQ in most. The current study demonstrates that buprenorphine accumulates into CNS tissues at much higher concentrations than in plasma in pregnant sheep, fetuses, and their newborn lambs even 45 hours after delivery.
European journal of pharmaceutical sciences
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
This work was supported by the Olvi Foundation, Iisalmi, Finland, The Finnish Concordia Fund, Helsinki, Finland, and the School of Pharmacy at University of Eastern Finland, Kuopio, Finland.
© 2022 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).