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: 7924517
• 负责人: KENNERLY Sexton PATRICK
• 金额: $ 28.42万
• 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 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7924517
• 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; 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）：现在已经众所周知，注意力缺陷多动症（ADHD）的频繁持续存在。适用于这种年龄较大的多动症人群的适当药物疗法需要特别考虑生活方式和生命跨度合并症。酒精使用障碍（AUD）和/或药物使用障碍（SUD）可能会使治疗变得复杂。 AUD和SUD在成人多动症中均具有过多的代表，尤其是在女性中。 DL甲酯（MPH）是多动症的首选药物。与1995 - 2002年相关的相关急诊室访问数量为每年的千年，乙醇（ETOH）与药物总体上的乙醇（ETOH）综合为期63％，年龄在18-19岁，在此期间为45-54岁的100％。本提案将表征MPH和ETOH之间新发现的药物相互作用的机制，并表征MPH性二态性的系统。这很重要，因为：（a）我们发现ETOH抑制酯酶介导的DL-MPH代谢，尤其是与女性相比的男性。这导致血浆MPH浓度显着升高（D-MPH> L-MPH）； （b）ETOH还用作DL-MPH酯交换酯酶的底物，以产生新型的活性代谢物乙二烯酸酯（等离子体L-l-eph> d-eph）； （c）我们发现，在延长释放（ER）配方中使用MPH时，女性的口服生物利用度明显低于男性，但在服用即时释放（IR）-MPH时却没有。我们的具体目的是：（1）确定 /-MPH是否负责ETOH后血浆D-MPH的升高； （2）确定有或没有ETOH的MPH的系统前代谢部位； （3）表征MPH-ETOH与C57小鼠模型的相互作用。我们的发现在临床药理学中的应用将有助于对ADHD疗法的优化，因为它与性别和与ETOH相互作用有关，例如使用IR-MPH和DL-MPH和DL-MPH与D-MPH配方。合并症ADHD/AUD患者可能会成为苯丙胺或非刺激治疗（例如蛋白酶）的一线候选者。最后，这些基本研究将有助于了解MPH-ETOH毒理学对于避免不良药物事件/死亡和伴随过量的合理紧急管理至关重要。例如，在没有知情的治疗干预措施的情况下，ETOH诱导的血浆MPH升高可能使患者容易患者发生心血管事故。

项目成果

Transdermal and oral dl-methylphenidate-ethanol interactions in C57BL/6J mice: transesterification to ethylphenidate and elevation of d-methylphenidate concentrations.

• DOI: 10.1002/jps.22476
• 发表时间: 2011-07
• 期刊: JOURNAL OF PHARMACEUTICAL SCIENCES
• 影响因子: 3.8
• 作者: Bell, Guinevere H.;Novak, Andrew J.;Griffin, William C., III;Patrick, Kennerly S.
• 通讯作者: Patrick, Kennerly S.

The interactive effects of methylphenidate and ethanol on ethanol consumption and locomotor activity in mice.

• DOI: 10.1016/j.pbb.2010.01.009
• 发表时间: 2010-05
• 期刊: PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR
• 影响因子: 3.6
• 作者: Griffin, William C., III;Novak, Andrew J.;Middaugh, Lawrence D.;Patrick, Kennerly S.
• 通讯作者: Patrick, Kennerly S.

Interactive effects of methylphenidate and alcohol on discrimination, conditioned place preference and motor coordination in C57BL/6J mice.

• DOI: 10.1007/s00213-012-2849-z
• 发表时间: 2013-02
• 期刊: PSYCHOPHARMACOLOGY
• 影响因子: 3.4
• 作者: Griffin, William C., III;McGovern, Robin W.;Bell, Guinevere H.;Randall, Patrick K.;Middaugh, Lawrence D.;Patrick, Kennerly S.
• 通讯作者: Patrick, Kennerly S.

The discriminative stimulus properties of methylphenidate in C57BL/6J mice.

• DOI: 10.1097/fbp.0b013e3283423d92
• 发表时间: 2011-02
• 期刊: Behavioural pharmacology
• 影响因子: 1.6
• 作者: McGovern RW;Middaugh LD;Patrick KS;Griffin WC 3rd
• 通讯作者: Griffin WC 3rd

Enantiospecific determination of DL-methylphenidate and DL-ethylphenidate in plasma by liquid chromatography-tandem mass spectrometry: application to human ethanol interactions.

• DOI: 10.1016/j.jchromb.2011.02.033
• 发表时间: 2011-04-01
• 期刊: JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES
• 影响因子: 3
• 作者: Zhu, Hao-Jie;Patrick, Kennerly S.;Markowitz, John S.
• 通讯作者: Markowitz, John S.