Elucidating High Oral Fluid Exposure Mechanisms of Buprenorphine to Reduce Dental Caries

摘要 阿片类药物使用障碍(OUD)在美国具有破坏性和悲剧性影响。只有三种药 作为药物辅助治疗(MAT)的一部分，最新的药物是丁丙诺啡。 丁丙诺啡主要以舌下片剂和片剂的形式给药。据估计，超过100万的口腔 丁丙诺啡处方是在2018年填写的。多份报告显示丁丙诺啡在高剂量下 口服(舌下)丁丙诺啡后口服液中的浓度通常高出10-100倍 而不是它的血浆浓度。阿片类似物的高口腔液体暴露是众所周知的，并被用来监测 阿片类药物在人体内的存在。最近，慢性口服丁丙诺啡的一个鲜为人知的副作用出现了 报警器。2022年1月，FDA发布警告称，口服丁丙诺啡制剂(即， 舌下药片和薄膜)可能会对牙齿造成严重伤害，有很大比例的患者是 服用这些丁丙诺啡配方。这对OUD患者来说是一个严重的问题，因为有效的 这一人群的药物治疗选择有限。如果不了解这种严重的疾病的机制 副作用影响使用者的健康和生活质量，很难开发出有效的药理作用 对策。造成牙齿损伤的机制尚不清楚，但我们 怀疑是由口服液中高浓度的丁丙诺啡引起的。我们假设 丁丙诺啡高剂量口腔液暴露的机制可被阐明，口腔液暴露 可以通过唾液刺激剂显著减少丁丙诺啡的暴露，而不会降低其全身 曝光。此外，减少口服液药物暴露将导致啮齿动物模型中龋齿的减少。 龋齿。我们还假设，丁丙诺啡在唾液腺中的高度积聚会增加口腔分泌物。 暴露于丁丙诺啡并抑制其在唾液腺中的蓄积将减少他们的口腔液 曝光。一种对不同浓度丁丙诺啡有反应的龋齿小鼠模型 建立并用于评估丁丙诺啡高剂量口服液暴露对儿童龋病的影响 老鼠。研究团队在研究药物葡萄糖醛酸化反应(丁丙诺啡被广泛使用)方面有丰富的经验 葡萄糖醛酸化)和转运体介导的药物处置，并配备适当的剂型(例如， 口腔底片)和专业知识(用于生物分析和质谱分析的LC-MS)，以了解口腔液暴露如何 丁丙诺啡可以减少。我们的功效研究将由一位有研究专长的牙医科学家领导 变形链球菌的毒力，一种主要的致龋物。我们的研究旨在开发“药理学” 方法“使用现有的动物模型支持药物发现和/或重新调整药物的用途 对牙齿健康有最小或很小负面影响的药物疗法。换句话说，我们的研究可能 导致未来选择药物来降低丁丙诺啡的口腔浓度，而不会产生负面影响 影响药物的全身暴露及其在药物辅助治疗中的预期用途。

SUMMARY Opioid use disorders (OUD) are having devastating and tragic effects in the USA. There are only three drugs available as a part of medication assisted treatment (MAT), and the newest drug is buprenorphine. Buprenorphine is mostly given as sublingual tablets and films. It is estimated that more than 1 million oral buprenorphine prescriptions were filled in 2018. Multiple reports suggest that buprenorphine is present in high concentrations in the oral fluids after oral (sublingual) buprenorphine administration, typically 10-100 folds higher than its plasma concentrations. The high oral fluid exposure to opioid analogs is well known and used to monitor the presence of opioids in people. Recently, a less known side effects of chronic oral buprenorphine use raised alarm. In January of 2022, FDA issued a warning stating that use of oral buprenorphine formulations (i.e., sublingual tablets and films) may cause serious harm to the teeth in significant percentages of patients who are taking these buprenorphine formulations. This is serious problem for OUD patients because the effective pharmacotherapy options for this population are limited. Without understanding the mechanism of this severe side effects that impact users' health and quality of life, it is difficult to develop effective pharmacological countermeasures. The mechanisms responsible for observed tooth damaging effects are unknown, but we suspected that it is caused by high concentrations of buprenorphine in the oral fluids. We hypothesize that mechanisms responsible for high oral fluid exposure to buprenorphine can be elucidated and oral fluid exposure to buprenorphine exposure can be significantly reduced by saliva stimulant without reducing their systemic exposure. Moreover, the reduced oral fluid drug exposure will lead to fewer dental caries in rodent models of caries. We also hypothesize that high accumulation of buprenorphine in salivary glands elevates oral fluid exposure to buprenorphine and inhibition of their accumulation in the salivary glands will reduce their oral fluid exposure. A mouse model of dental caries that are responsive to varying concentrations of buprenorphine will be established and use to evaluate the impact of high oral fluid exposure to buprenorphine on dental caries in mice. The study team has a rich experience in studying drug glucuronidation (buprenorphine is extensively glucuronidated), and transporter-mediated drug disposition, and is equipped with the proper dosage form (e.g., oral film) and expertise (LC-MS for bioanalysis and mass spectrometry) to understand how oral fluid exposure to buprenorphine could be reduced. Our efficacy study will be led by a dentist-scientist with expertise in studying the virulence of Streptococcus mutans, a primary cariogen. Our study aims to develop “pharmacologic approaches” using the current animal models to support drug discovery and/or repurposing for OUD pharmacotherapeutics with minimal or minor negative impact on dental health. In other words, our research may lead to future selection of drugs to reduce oral cavity concentrations of buprenorphine without negatively impacting the drug's systemic exposure and its intended use for medication assisted treatment in OUD.