School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
School of Pharmacy, University of Eastern Finland, Kuopio, Finland.
Eur J Pharm Sci. 2022 Nov 1;178:106283. doi: 10.1016/j.ejps.2022.106283. Epub 2022 Aug 24.
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.
布比卡因在孕期用于治疗阿片类药物使用障碍。关于布比卡因向中枢神经系统（CNS）渗透和分布，以及胎儿对布比卡因的暴露，目前的数据有限。我们的研究目的是确定在稳定状态下，不同剂量方案下，怀孕绵羊及其胎儿和分娩后新生羔羊的布比卡因向中枢神经系统的分布程度。28 只妊娠晚期的绵羊接受了为期 7 天的透皮贴剂布比卡因治疗，每 24 小时释放 20μg/h（n=9）或 40μg/h（n=11），或每周皮下注射 8mg 缓释剂（n=8）。在稳定状态下从母羊和胎儿以及分娩后 0.33-45 小时从羔羊收集血浆、脑脊液和中枢神经系统组织样本。在所有中枢神经系统组织中都观察到布比卡因的高度蓄积。不同中枢神经系统区域布比卡因的中枢神经系统/血浆浓度比值中位数在母羊中为 13-50，在胎儿中为 26-198。在母羊中，三种剂量方案后的中枢神经系统/血浆比值相似，但在 40μg/h 剂量组中的胎儿中更高，中位数为 65-122，而在 20μg/h 组中为 26-54。皮下注射（理论释放率为 47.6μg/h）产生的浓度高于 40μg/h 透皮贴剂给药后的观察结果。不同剂量组的胎儿/母体浓度比值在血浆中范围为 0.21-0.54，在中枢神经系统组织中范围为 0.38-1.3，脊髓中观察到的比值最高。布比卡因在母羊脑脊液中的浓度为同期血浆浓度的 8-13%，在胎儿中为 28%。布比卡因可在分娩后两天从新生羔羊的血浆和中枢神经系统组织中定量检测。从所有血浆、脑脊液和中枢神经系统组织样本中分析了诺布比卡因，但在大多数样本中均无法检测到或低于LLOQ。本研究表明，即使在分娩后 45 小时，布比卡因在怀孕绵羊、胎儿及其新生羔羊的中枢神经系统组织中的积累浓度也远远高于血浆。
