Department of Internal Medicine, Division of Clinical Pharmacology, Södersjukhuset, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
Ther Drug Monit. 2008 Oct;30(5):565-9. doi: 10.1097/FTD.0b013e31818679c9.
Studies that focus on multidrug interactions in natural settings are sparse. In this investigation, data from therapeutic drug monitoring (TDM) were used to study the impact of multiple cytochrome P450 enzyme (CYP) 2D6 substrates and inhibitors on plasma risperidone levels. CYP2D6 catalyzes the conversion of risperidone to the active metabolite 9-OH-risperidone. The question whether CYP2D6 activity is important for the level of the "active moiety" (ie, the sum of risperidone and 9-OH-risperidone) is controversial. Concentration-to-dose (C:D) ratios of risperidone and 9-OH-risperidone in 218 patients were associated with the number of concomitantly used substrates or inhibitors of CYP2D6. The C:D ratios of risperidone in patients with 0, 1, and >1 numbers of CYP2D6 inhibitors were 2.6, 8.5, and 17 nmol L mg, respectively. Differences between the groups were highly significant (P < 0.001). All patients with >1 CYP2D6 inhibitors were administered at least 1 potent CYP2D6 inhibitor, that is fluoxetine, paroxetine, thioridazine, and/or levomepromazine. The C:D ratios of the active moiety (risperidone + 9-OH-risperidone) in patients with 0, 1, and >1 numbers of concomitant CYP2D6 inhibitors were 17, 24, and 30 nmol L mg, respectively (P = 0.001), which was explained by higher levels of risperidone without any change in the levels of 9-OH-risperidone. Concomitant use of 1 or several drugs recognized as substrates for CYP2D6, without any proven inhibitory effect, had no apparent influence on the levels of risperidone or 9-OH-risperidone, suggesting that the risk of drug-drug interactions between different substrates of CYP2D6 is low when used in therapeutic doses. In conclusion, the results suggest that an increase in the number of concomitant inhibitors may be associated with a lower CYP2D6 activity, although the type of inhibitor is probably more important. Drug-dependent inhibition of CYP2D6 increases the active moiety of risperidone. An indication for risperidone TDM should therefore include concomitant medication with established CYP inhibitors.
在自然环境中研究多种药物相互作用的研究很少。在这项研究中，使用治疗药物监测 (TDM) 数据来研究多种细胞色素 P450 酶 (CYP) 2D6 底物和抑制剂对血浆利培酮水平的影响。CYP2D6 催化利培酮转化为活性代谢物 9-OH-利培酮。CYP2D6 活性是否对“活性部分”（即利培酮和 9-OH-利培酮的总和）水平重要存在争议。218 名患者的利培酮和 9-OH-利培酮的浓度与剂量 (C:D) 比值与同时使用的 CYP2D6 底物或抑制剂的数量有关。CYP2D6 抑制剂数量为 0、1 和 >1 的患者的利培酮 C:D 比值分别为 2.6、8.5 和 17 nmol L mg。组间差异具有高度显著性 (P < 0.001)。所有使用 >1 种 CYP2D6 抑制剂的患者均至少使用了 1 种强效 CYP2D6 抑制剂，即氟西汀、帕罗西汀、噻吨和/或左美丙嗪。同时使用 0、1 和 >1 种 CYP2D6 抑制剂的患者的活性部分（利培酮+9-OH-利培酮）的 C:D 比值分别为 17、24 和 30 nmol L mg（P = 0.001），这是由于利培酮水平升高而 9-OH-利培酮水平无变化所致。同时使用 1 种或多种被认为是 CYP2D6 底物的药物，且无任何已证实的抑制作用，对利培酮或 9-OH-利培酮水平无明显影响，提示 CYP2D6 不同底物之间发生药物-药物相互作用的风险较低，当以治疗剂量使用时。总之，结果表明，同时使用的抑制剂数量增加可能与 CYP2D6 活性降低有关，尽管抑制剂的类型可能更为重要。CYP2D6 的药物依赖性抑制增加了利培酮的活性部分。因此，利培酮 TDM 的指征应包括同时使用已确定的 CYP 抑制剂。
