Methylphenidate-Ethanol Interactions in ADHD and Co-abuse

哌甲酯-乙醇在 ADHD 和共同滥用中的相互作用

• 批准号: 7683243
• 负责人: KENNERLY Sexton PATRICK
• 金额: $ 28.71万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7683243
• 关键词: Accident and Emergency department; Accidents; Adult; Age; Alcohol consumption; Amphetamines; Attention deficit hyperactivity disorder; Biological Availability; Brain; Cardiovascular system; Clinical; Clinical Pharmacology; Communities; Comorbidity; Dose; Drug Combinations; Drug Formulations; Drug Interactions; Drug Kinetics; Drug Prescriptions; Emergency Situation; Enteral; Ethanol; Event; Gender; Hepatic; Human; Hydrolysis; Incidence; Intervention; Intestines; Investigation; Isomerism; Life Style; Liver; Longevity; Mediating; Metabolism; Methylphenidate; Morbidity - disease rate; Nature; Oral; Overdose; Patients; Persons; Pharmaceutical Preparations; Pharmacodynamics; Pharmacotherapy; Plasma; Population; Prevalence; Relative (related person); Research; Research Personnel; Rewards; Risk; Site; Stroke; Substance Use Disorder; System; Testing; Toxicology; Visit; Woman; aged; alcohol pharmacology; alcohol use disorder; atomoxetine; base; esterase; ethylphenidate; men; mouse model; novel; programs; sexual dimorphism

DESCRIPTION (provided by applicant): The frequent persistence of attention-deficit hyperactivity disorder (ADHD) into adulthood is now well recognized. Appropriate drug therapy for this older ADHD population requires a special consideration of lifestyle and life span comorbidity. Treatment may be complicated by alcohol use disorder (AUD) and/or substance use disorder (SUD). Both AUD and SUD are over-represented in adult ADHD, especially in women. dl-Methylphenidate (MPH) is the drug of choice for ADHD. MPH related emergency department visits number in the thousands per year from 1995-2002, and ethanol (ETOH)-in-combination with drugs in general has risen 63% for ages18-19 and 100% for ages 45-54 during this period. The present proposal will characterize mechanisms underlying a newly discovered drug interaction between MPH and ETOH, as well as characterize the systems underlying MPH sex dimorphism. This is important because: (a) We have found that ETOH inhibits the esterase mediated metabolism of dl-MPH, especially in men compared to women. This results in significantly elevated plasma MPH concentrations (d-MPH>l-MPH); (b) ETOH also serves as a substrate for the esterase(s) in the transesterification of dl-MPH to yield the novel active metabolite ethylphenidate (plasma l-EPH>d-EPH); (c) We have found that women have significantly lower oral bioavailability than men when dosed with MPH in extended-release (ER) formulations, but not when dosed with immediate-release (IR)-MPH. Our SPECIFIC AIMS are to: (1) determine if /-MPH is responsible for the elevation of plasma d-MPH after ETOH; (2) determine the sites of presystemic metabolism of MPH with and without ETOH; and (3) characterize MPH-ETOH interactions with C57 mouse models. Application of our findings to clinical pharmacology will contribute to the optimization of ADHD therapy as it relates to gender and interaction with ETOH, e.g., use of IR- vs. ER-MPH and dl-MPH vs. d-MPH formulations. Comorbid ADHD/AUD patients may become first-line candidates for amphetamine or non-stimulant therapy such as atomoxetine. Finally, these basic investigations will contribute to an understanding of MPH-ETOH toxicology essential for avoidance of adverse drug events/fatalities, and for the rational emergency management of concomitant overdose. For instance, ETOH induced elevation of plasma MPH may predispose a patient to cardiovascular accidents in the absence of informed treatment interventions.

描述（由申请人提供）：现已广泛认识到，注意力缺陷多动障碍 (ADHD) 经常持续到成年期。对老年多动症人群进行适当的药物治疗需要特别考虑生活方式和寿命合并症。酒精使用障碍 (AUD) 和/或物质使用障碍 (SUD) 可能会使治疗变得复杂。 AUD 和 SUD 在成人 ADHD 中所占比例过高，尤其是女性。 dl-哌甲酯 (MPH) 是治疗 ADHD 的首选药物。从 1995 年到 2002 年，每年与 MPH 相关的急诊科就诊人数达到数千人次，在此期间，18-19 岁的乙醇 (ETOH) 与一般药物的联合使用增加了 63%，45-54 岁的则增加了 100%。本提案将描述 MPH 和 ETOH 之间新发现的药物相互作用的机制，以及描述 MPH 性别二态性背后的系统。这很重要，因为： (a) 我们发现 ETOH 抑制酯酶介导的 dl-MPH 代谢，尤其是男性与女性相比。这导致血浆 MPH 浓度显着升高（d-MPH>l-MPH）； (b) ETOH 还充当 dl-MPH 酯交换反应中酯酶的底物，产生新型活性代谢物哌乙酯（血浆 l-EPH>d-EPH）； (c) 我们发现，当服用缓释 (ER) 制剂中的 MPH 时，女性的口服生物利用度显着低于男性，但服用速释 (IR)-MPH 时则不然。我们的具体目标是：（1）确定 1-MPH 是否是 ETOH 后血浆 d-MPH 升高的原因； (2) 确定有或没有 ETOH 情况下 MPH 的系统前代谢位点； (3) 表征 MPH-ETOH 与 C57 小鼠模型的相互作用。将我们的研究结果应用于临床药理学将有助于 ADHD 治疗的优化，因为它与性别和与 ETOH 的相互作用有关，例如使用 IR-与 ER-MPH 以及 dl-MPH 与 d-MPH 制剂。共病 ADHD/AUD 患者可能成为安非他明或阿托西汀等非兴奋剂治疗的一线候选者。最后，这些基本研究将有助于了解 MPH-ETOH 毒理学，这对于避免药物不良事件/死亡以及对伴随用药过量的合理应急管理至关重要。例如，在缺乏知情治疗干预的情况下，ETOH 引起的血浆 MPH 升高可能会使患者容易发生心血管事故。