Methylphenidate-Ethanol Interaction in ADHD and Coabuse

哌甲酯-乙醇在 ADHD 和 Coabuse 中的相互作用

• 批准号: 6668718
• 负责人: KENNERLY Sexton PATRICK
• 金额: $ 25.55万
• 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 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6668718
• 关键词: adult human (21+); alcoholic beverage consumption; alcoholism /alcohol abuse; attention deficit disorder; behavior test; central nervous system stimulants; clinical research; comorbidity; drug interactions; drug metabolism; ethanol; gas chromatography mass spectrometry; gender difference; human subject; laboratory mouse; methylphenidate; neuropharmacology; patient oriented research; pharmacokinetics; stereoisomer; substance abuse related disorder; toxicology

DESCRIPTION (provided by applicant): Appropriate drug therapy for attention-deficit hyperactivity disorder (ADHD) requires special consideration of lifestyle and life span comorbidity. (1) dI-Methylphenidate (MPH) is a drug of choice for ADHD; (2) Substance/alcohol abuse and dependence is over-represented in adolescent and adult ADHD, especially in women; (3) A pilot study revealed a novel MPH-ethanol metabolic drug interaction, wherein ethanol combines with MPH to form ethylphenidate (ETPH); and (4) the ethanol also appeared to inhibit MPH metabolism (especially in the female subjects; women have been reported to exhibit reduced first-pass metabolism of ethanol). Given these considerations, the potential therapeutic and toxicological significance of the MPH-ethanol interaction is proposed for investigation. SPECIFIC AIM 1 is to test the hypothesis that the enantiomers of the metabolite ETPH contribute to the neuropharmacology of concomitant MPH-ethanol. Monoamine transporter inhibition and mouse behavioral screens will be used for this assessment. SPECIFIC AIM 2 will test the hypothesis that ETPH will be formed enantioselectively. Enantiospecific gas chromatography-mass spectrometry (GC-MS)-negative ion chemical ionization will be used to simultaneously quantitate d-MPH, I-MPH, d-ETPH and I-ETPH from serial plasma samples. Healthy human volunteers-eight men and eight women--will participate in these pharmacokinetic studies. SPECIFIC AIM 3 (a) will ask what extent the MPH-ethanol interaction increases MPH blood concentrations in men vs. women; (b) will test the prediction that ethanol will not only elevate total plasma MPH levels, but also reduce the plasma d-MPH/I-MPH ratio; and (c) will test the hypothesis that the order of administration of ethanol relative to MPH influences the extent of this drug interaction (in the same order-dependent manner that has been reported for the cocaine-ethanol interaction which forms cocaethylene and can inhibit cocaine metabolism). The findings will serve to broaden our understanding of the toxicological consequences of MPH-ethanol coabuse and contribute to the rational emergency management of this common concomitant drug overdose. Further, the results will be used to support recommendations for optimal drug individualization in the treatment of ADHD, e.g., dextroamphetamine vs. MPH; dI-MPH vs. d-MPH; immediate-release MPH vs. extended-release MPH; or adjustment of MPH.

描述（由申请人提供）：针对缺乏注意力障碍（ADHD）的适当药物治疗需要特别考虑生活方式和生命跨度合并症。 （1）二甲酯（MPH）是多动症的首选药物； （2）青少年和成人多动症中的物质/酗酒和依赖性过多，尤其是在女性中； （3）一项试点研究揭示了一种新型的MPH-乙醇代谢药物相互作用，其中其中乙醇与MPH结合形成乙酰苯甲酸甲酯（ETPH）； （4）乙醇似乎也抑制了MPH的代谢（尤其是在女性受试者中；据报道，妇女表现出乙醇的第一通道代谢）。考虑到这些考虑，提出了MPH-乙醇相互作用的潜在治疗和毒理学意义进行研究。 具体目的1是检验以下假设：代谢物ETPH的对映异构体有助于伴随MPH-乙醇的神经药理。 单胺转运蛋白抑制和小鼠行为筛选将用于此评估。 特定的目标2将检验将ETPH形成对映射的假设。对映体气相色谱 - 质量质谱法（GC-MS）阴性化学电离将用于同时定量串行等离子体样品中的D-MPH，I-MPH，D-ETPH和I-ETPH。健康的人类志愿者 - 八名男性和八名女性 - 将参加这些药代动力学研究。 具体目标3（a）将询问MPH-乙醇相互作用在多大程度上增加男性与女性的MPH血液浓度； （b）将测试乙醇不仅会提高总血浆MPH水平的预测，还将降低血浆D-MPH/I-MPH比率； （c）将检验以下假设：乙醇相对于MPH的施用顺序会影响这种药物相互作用的程度（以相同的顺序依赖性方式，已报告的可卡因 - 乙醇相互作用，形成可卡因乙烯并可以抑制可卡因的代谢）。这些发现将扩大我们对MPH-乙醇兼容的毒理学后果的理解，并为这种常见的伴随药物过量的合理紧急管理做出贡献。此外，该结果将用于支持在治疗多动症中最佳药物个性化的建议，例如右旋苯丙胺与MPH； DI-MPH vs. D-MPH；立即释放MPH与扩展释放MPH；或调整MPH。

项目成果

Evolution of stimulants to treat ADHD: transdermal methylphenidate.

• DOI: 10.1002/hup.992
• 发表时间: 2009-01
• 期刊: HUMAN PSYCHOPHARMACOLOGY-CLINICAL AND EXPERIMENTAL
• 影响因子: 1.7
• 作者: Patrick, Kennerly S.;Straughn, Arthur B.;Perkins, Jeb S.;Gonzalez, Mario A.
• 通讯作者: Gonzalez, Mario A.

Ethanol Interactions With Dexmethylphenidate and dl-Methylphenidate Spheroidal Oral Drug Absorption Systems in Healthy Volunteers.

• DOI: 10.1097/jcp.0000000000000721
• 发表时间: 2017-08
• 期刊: Journal of clinical psychopharmacology
• 影响因子: 2.9
• 作者: Zhu HJ;Patrick KS;Straughn AB;Reeves OT 3rd;Bernstein H;Shi J;Johnson HJ;Knight JM;Smith AT;Malcolm RJ;Markowitz JS
• 通讯作者: Markowitz JS

Methylphenidate and its ethanol transesterification metabolite ethylphenidate: brain disposition, monoamine transporters and motor activity.

哌甲酯及其乙醇酯交换代谢物哌甲酯：大脑处置、单胺转运蛋白和运动活动。

• DOI: 10.1097/fbp.0b013e3280143226
• 发表时间: 2007
• 期刊: Behavioural pharmacology
• 影响因子: 1.6
• 作者: Williard,RobinL;Middaugh,LawrenceD;Zhu,Hao-JieB;Patrick,KennerlyS
• 通讯作者: Patrick,KennerlyS