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

阐明丁丙诺啡的高口腔液暴露机制以减少龋齿

• 批准号: 10765181
• 负责人: MING HU
• 金额: $ 143.41万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2025-09-20
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10765181
• 关键词: Affect; Animal Model; Attention; Behavior Therapy; Biodistribution; Buprenorphine; Chronic; Cimetidine; Counseling; Data; Dental caries; Dentists; Dosage Forms; Dose; Drug Exposure; Drug toxicity; Drug usage; Effectiveness; Emergency Situation; Environment; Excretory function; Exposure to; FDA approved; Film; Formulation; Future; Gland; Goals; Grant; Health; Hour; Human; Image; Implant; Injections; Knockout Mice; Liquid substance; Mass Spectrum Analysis; Mediating; Medical; Methadone; Minor; Monitor; Mus; Naltrexone; Natural Products; Opioid; Oral; Oral cavity; Oral health; Organ; Organic Cation Transporter; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacotherapy; Plasma; Population; Quality of life; Reporting; Research; Rodent; Rodent Model; Role; Saliva; Salivary Glands; Scientist; Spatial Distribution; Stimulant; Streptococcus mutans; Sublingual drug administration; Substance Use Disorder; Tablets; Time; Tissues; Tooth structure; Virulence; analog; design; drug discovery; drug disposition; drug repurposing; efficacy study; experience; in vivo; in vivo Model; inhibitor; medication-assisted treatment; mouse model; opioid use disorder; oral tissue; pathogen; pharmacologic; quorum sensing; side effect; subcutaneous; success

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.

总结 阿片类药物使用障碍（OUD）在美国产生了毁灭性和悲剧性的影响。只有三种药物 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薄膜形式提供。据估计，超过100万的口服 丁丙诺啡处方于2018年填写。多份报告表明，丁丙诺啡存在于高 口服（舌下）丁丙诺啡给药后，口服液中的浓度通常高10-100倍 比血浆浓度更高阿片类药物类似物的高口服液暴露是众所周知的，并用于监测 阿片类药物在人体内的存在最近，一个鲜为人知的副作用慢性口服丁丙诺啡使用提高 警报2022年1月，FDA发布警告称，使用口服丁丙诺啡制剂（即， 舌下片剂和薄膜）可能会导致严重伤害牙齿的患者的显着百分比， 服用这些丁丙诺啡制剂这对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 副作用，影响用户的健康和生活质量，很难开发有效的药理学 对策负责观察到的牙齿损伤影响的机制是未知的，但我们 怀疑是由口腔液中高浓度的丁丙诺啡引起的。我们假设 可以阐明导致丁丙诺啡高口服液暴露的机制， 唾液刺激剂可以显著降低丁丙诺啡暴露，而不会降低其全身性 exposure.此外，减少的口腔流体药物暴露将导致啮齿动物模型中更少的龋齿。 龋齿我们还假设，唾液腺中丁丙诺啡的高积累会升高口腔液 暴露于丁丙诺啡并抑制其在唾液腺中的积累将减少他们的口腔液 exposure.对不同浓度的丁丙诺啡有反应的龋齿小鼠模型将 建立并用于评估高口腔液暴露于丁丙诺啡对龋齿的影响， 小鼠研究团队在药物葡萄糖醛酸化研究方面经验丰富（丁丙诺啡广泛用于 葡萄糖醛酸化的）和转运蛋白介导的药物处置，并且配备有适当的剂型（例如， 口腔胶片）和专业知识（用于生物分析和质谱分析的LC-MS），以了解口腔液体暴露 对丁丙诺啡的耐受性可以降低我们的疗效研究将由一位牙科科学家领导，他在研究 变形链球菌的毒力，一种主要的致龋原。我们的研究旨在开发“药理学” 方法”使用当前的动物模型来支持药物发现和/或重新利用OUD 对牙齿健康具有最小或轻微负面影响的药物治疗。换句话说，我们的研究可能 导致将来选择药物来降低丁丙诺啡口腔浓度，而不产生负面影响 影响药物的全身暴露及其用于OUD药物辅助治疗的预期用途。