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: 6557843
• 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 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6557843
• 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）：针对注意力缺陷多动障碍（ADHD）的适当药物治疗需要特别考虑生活方式和寿命期间的合并症。 （1）dI-哌甲酯（MPH）是治疗ADHD的首选药物； (2) 物质/酒精滥用和依赖在青少年和成人多动症中所占比例过高，特别是在女性中； (3) 一项初步研究揭示了一种新型的MPH-乙醇代谢药物相互作用，其中乙醇与MPH结合形成哌乙酯(ETPH)； (4) 乙醇似乎也抑制 MPH 代谢（特别是在女性受试者中；据报道，女性表现出乙醇首过代谢减少）。考虑到这些因素，建议研究 MPH-乙醇相互作用的潜在治疗和毒理学意义。 具体目标 1 是检验以下假设：代谢物 ETPH 的对映体有助于伴随的 MPH-乙醇的神经药理学。 单胺转运蛋白抑制和小鼠行为筛选将用于此评估。 具体目标 2 将测试 ETPH 将以对映选择性形成的假设。对映特异性气相色谱-质谱 (GC-MS)-负离子化学电离将用于同时定量系列血浆样品中的 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）将参与这些药代动力学研究。 具体目标 3 (a) 将询问 MPH-乙醇相互作用在男性与女性中增加 MPH 血液浓度的程度； (b) 将检验乙醇不仅会提高血浆总 MPH 水平，还会降低血浆 d-MPH/I-MPH 比率的预测； (c) 将检验以下假设：相对于 MPH，乙醇的给药顺序会影响这种药物相互作用的程度（以与已报道的可卡因-乙醇相互作用相同的顺序依赖性方式，形成可卡乙烯并可以抑制可卡因）代谢）。这些发现将有助于扩大我们对 MPH-乙醇共滥用毒理学后果的理解，并有助于对这种常见的伴随药物过量进行合理的应急管理。此外，结果将用于支持 ADHD 治疗中最佳药物个体化的建议，例如右旋苯丙胺与 MPH； dI-MPH 与 d-MPH；立即释放 MPH 与缓释 MPH；或调整MPH。