This article provides an overview of the pharmacokinetic drug-drug interactions (DDIs) for agents prescribed for attention-deficit/hyperactivity disorder (ADHD). Polypharmacy in the treatment of patients with ADHD leads to high exposures to DDIs and possibly adverse safety outcomes. We performed a systematic search of DDI reports for ADHD agents in Embase and Medline. We also searched for agents in the pharmacological pipeline, which include (1) mazindol, molindone and viloxazine, which were previously prescribed for other indications; (2) centanafadine and AR-08, never before approved; and (3) two extracts (Polygala tenuifolia extract and the French maritime pine bark extracts). The identified literature included case reports, cross-sectional, cross-over and placebo-controlled studies of patient cohorts and healthy volunteers. The DDIs were classified as follows: ADHD agents acting as perpetrators, i.e., affecting the clearance of co-prescribed agents (victim drugs), or ADHD agents being the victim drugs, being affected by other agents. Ratios for changes in pharmacokinetic parameters before and after the DDI were used as a rough estimate of the extent of the DDI. Alcohol may increase plasma dextroamphetamine concentrations by presystemic effects. Until studies are done to orient clinicians regarding dosing changes, clinicians need to be aware of the potential for cytochrome P450 (CYP) 2D6 inhibitors to increase amphetamine levels, which is equivalent to increasing dosages. Atomoxetine is a wide therapeutic window drug. The CYP2D6 poor metabolizers who do not have CYP2D6 activity had better atomoxetine response, but also an increased risk of adverse effects. CYP2D6 inhibitors have been used to increase atomoxetine response in CYP2D6 extensive metabolizers. Guanfacine is mainly metabolized by CYP3A4, which can be induced and inhibited. The package insert recommends that in guanfacine-treated patients, after adding potent CYP3A4 inducers, the guanfacine dose should be doubled; after adding potent CYP3A4 inhibitors the guanfacine dose should be halved. Based on a phenobarbital case report and our experience with CYP3A4-metabolized antipsychotics, these correction factors may be too low. According to two case reports, carbamazepine is a clinically relevant inducer of methylphenidate (MPH). A case series study suggested that MPH may be associated with important elevations in imipramine concentrations. Due to the absence of or limitations in the data, no comments for clinicians can be provided on the pharmacokinetic DDIs for clonidine, centanafadine, mazindol, molindone, AR-08, P. tenuifolia extract and the French maritime pine bark extracts. According to currently available data, clinicians should not expect that ADHD drugs modify each other's serum concentrations. A summary table for clinicians provides our current recommendations on pharmacokinetic DDIs of ADHD agents based on our literature review and the package inserts; whenever it was possible, we provide information on serum concentrations and dose correction factors. There will be a need to periodically update these recommendations and these correction factors as new knowledge becomes available.

中文翻译：

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与注意力缺陷/多动症药物的临床意义重大的药物相互作用。

本文概述了注意缺陷/多动症（ADHD）处方药的药代动力学药物-药物相互作用（DDI）。多药治疗ADHD患者会导致DDI暴露过多，并可能导致不良安全后果。我们对Embase和Medline中的ADHD代理商进行了DDI报告的系统搜索。我们还搜索了药理产品线中的药物，其中包括（1）之前为其他适应症开出的mazindol，molindone和viloxazine。（2）从未批准的他那法定和AR-08；（3）两种提取物（Polygala tenuifolia提取物和法国海洋松树皮提取物）。确定的文献包括病例报告，对患者队列和健康志愿者的横断面，交叉和安慰剂对照研究。DDI的分类如下：ADHD试剂充当犯罪者，即影响共同处方药（受害者药物）的清除，或ADHD试剂是受害药物，并受到其他试剂的影响。DDI之前和之后药代动力学参数变化的比率用作DDI程度的粗略估计。酒精可能会通过系统前作用增加血浆右旋苯丙胺的浓度。在确定有关剂量变化的指导临床医生的研究之前，临床医生需要意识到细胞色素P450（CYP）2D6抑制剂增加苯丙胺水平的潜力，这等同于增加剂量。Atomoxetine是一种广泛的治疗窗口药物。没有CYP2D6活性的CYP2D6弱代谢者具有更好的阿托西汀反应，但同时增加了不良反应的风险。CYP2D6抑制剂已被用于增加CYP2D6广泛代谢者中的阿托西汀反应。胍法辛主要由CYP3A4代谢，可被诱导和抑制。包装说明书建议在胍法辛治疗的患者中，加入强效CYP3A4诱导剂后，胍法辛的剂量应加倍；加入强效CYP3A4抑制剂后，胍法辛剂量应减半。根据苯巴比妥病例报告和我们对CYP3A4代谢的抗精神病药的经验，这些校正因子可能太低。根据两个病例报告，卡马西平是临床上有关哌醋甲酯（MPH）的诱导剂。案例研究表明，MPH可能与丙咪嗪浓度的重要升高有关。由于数据的缺乏或限制，对于可乐定，倍他法定，mazindol，molindone，AR-08，P。tenuifolia提取物和法国海上松树皮提取物的药代动力学DDI，没有为临床医生提供任何评论。根据目前可获得的数据，临床医生不应期望ADHD药物会改变彼此的血清浓度。根据我们的文献综述和包装说明书，临床医生总结表提供了我们当前对ADHD药物的药代动力学DDI的建议；只要有可能，我们都会提供有关血清浓度和剂量校正因子的信息。随着新知识的获得，将需要定期更新这些建议和这些校正因子。根据目前可获得的数据，临床医生不应期望ADHD药物会改变彼此的血清浓度。根据我们的文献综述和包装说明书，临床医生总结表提供了我们当前对ADHD药物的药代动力学DDI的建议；只要有可能，我们都会提供有关血清浓度和剂量校正因子的信息。随着新知识的获得，有必要定期更新这些建议和这些校正因子。根据目前可获得的数据，临床医生不应期望ADHD药物会改变彼此的血清浓度。根据我们的文献综述和包装说明书，临床医生总结表提供了我们当前对ADHD药物的药代动力学DDI的建议；只要有可能，我们都会提供有关血清浓度和剂量校正因子的信息。随着新知识的获得，将需要定期更新这些建议和这些校正因子。我们提供有关血清浓度和剂量校正因子的信息。随着新知识的获得，将需要定期更新这些建议和这些校正因子。我们提供有关血清浓度和剂量校正因子的信息。随着新知识的获得，有必要定期更新这些建议和这些校正因子。