丁丙诺啡在唾液腺中的蓄积维持高口腔液体暴露并增加变形链球菌生物膜形成的风险。
Buprenorphine Salivary Gland Accumulation Sustaining High Oral Fluid Exposure and Increasing the Risk of Streptococcus mutans Biofilm Formation.
作者信息
Zheng Zicong, Chen Jie, Srinual Songpol, Tumbas Šaponjac Vesna, Yin Taijun, Wang Bing-Yan, Sun Rongjin, Hu Ming
机构信息
From the Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX (ZZ, JC, SS, VTŠ, TY, RS, MH); School of Dentistry, University of Texas Health Science Center at Houston, TX (BW).
出版信息
J Addict Med. 2024 Dec 2. doi: 10.1097/ADM.0000000000001401.
OBJECTIVES
The US Food and Drug Administration (FDA) issued a warning about buprenorphine-induced dental caries of unknown mechanism in 2022. To investigate the potential mechanism, the association between local buprenorphine exposure and dental biofilm formation will be explored in this study.
METHODS
Female F344 rats were dosed with sublingual buprenorphine film or intravenous injection to explore the oral cavity exposure of the buprenorphine. The buprenorphine distribution in salivary glands after the sublingual and intravenous administration was also evaluated. To investigate the effects of buprenorphine exposure on dental caries formation, buprenorphine's impact on the biofilm formation of S. mutans in vitro was measured.
RESULTS
The absolute sublingual bioavailability of buprenorphine in rats was 17.8% with a high ratio of oral fluid exposure to blood concentration in the pharmacokinetic study. Salivary gland concentrations of buprenorphine and its active metabolite norbuprenorphine were significantly higher than their blood concentrations after both sublingual (s.l.) and intravenous (i.v.) administration. Correlation analysis showed that the oral fluid concentration of buprenorphine and norbuprenorphine was highly correlated to salivary gland concentration rather than blood concentration. These data indicate that the salivary gland serves as an accumulation organ for buprenorphine, allowing prolonged oral fluid exposure to buprenorphine. Lastly, buprenorphine and its metabolites contributed to the biofilm formation of S. mutans in high concentration.
CONCLUSIONS
Sublingual administration substantially increased the salivary gland distribution of buprenorphine and norbuprenorphine. Depot effects following sublingual dosing and salivary gland accumulation likely sustained high oral fluid exposure to buprenorphine and stimulated the biofilm formation of S. mutans.
目的
美国食品药品监督管理局（FDA）于2022年发布了关于丁丙诺啡导致不明机制龋齿的警告。为研究潜在机制，本研究将探讨局部丁丙诺啡暴露与牙菌斑形成之间的关联。
方法
对雌性F344大鼠给予丁丙诺啡舌下膜剂或静脉注射，以探究丁丙诺啡的口腔暴露情况。还评估了舌下给药和静脉给药后丁丙诺啡在唾液腺中的分布。为研究丁丙诺啡暴露对龋齿形成的影响，测定了丁丙诺啡对变形链球菌生物膜形成的体外影响。
结果
在药代动力学研究中，丁丙诺啡在大鼠中的绝对舌下生物利用度为17.8%，口腔液暴露与血药浓度之比很高。舌下给药（s.l.）和静脉给药（i.v.）后，丁丙诺啡及其活性代谢物去甲丁丙诺啡在唾液腺中的浓度均显著高于其血药浓度。相关性分析表明，丁丙诺啡和去甲丁丙诺啡的口腔液浓度与唾液腺浓度高度相关，而非与血药浓度相关。这些数据表明，唾液腺是丁丙诺啡的蓄积器官，使口腔液能够长时间暴露于丁丙诺啡。最后，丁丙诺啡及其代谢物在高浓度下促进了变形链球菌的生物膜形成。
结论
舌下给药显著增加了丁丙诺啡和去甲丁丙诺啡在唾液腺中的分布。舌下给药后的贮库效应和唾液腺蓄积可能使口腔液长时间高浓度暴露于丁丙诺啡，并刺激了变形链球菌的生物膜形成。
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