Abstract：
OBJECTIVE: Metamizole is quite an old drug with analgesic, antipyretic and spasmolytic properties. Recent findings have shown that it may induce several cytochrome P450 (CYP) enzymes, especially CYP3A4 and CYP2B6. The clinical relevance of these properties is uncertain. We aimed to unravel potential pharmacokinetic interactions between metamizole and the CYP3A4 substrate quetiapine.
METHODS: Plasma concentrations of quetiapine from a large therapeutic drug monitoring database were analysed. Two groups of 33 patients, either receiving quetiapine as a monotherapy (without CYP modulating comedications) or with concomitantly applied metamizole, were compared addressing a potential impact of metamizole on the metabolism of quetiapine being reflected in differences of plasma concentrations of quetiapine and dose-adjusted plasma concentrations.
RESULTS: Patients comedicated with metamizole showed >50% lower plasma concentrations of quetiapine (median 45.2 ng/mL, Q1 = 15.5; Q3 = 90.5 vs. 92.0 ng/mL, Q1 = 52.3; Q3 = 203.8, P = .003). The dose-adjusted plasma concentrations were 69% lower in the comedication group (P = .001). Subgroup analyses did not suggest a dose dependency of the metamizole effect or an influence of quetiapine formulation (immediate vs. extended release). Finally, the comedication group exhibited a significantly higher proportion of patients whose quetiapine concentrations were below the therapeutic reference range (78.8% in the metamizole group vs. 54.4% in the control group, P = .037) indicating therapeutically insufficient drug concentrations.
CONCLUSIONS: The combination of metamizole and quetiapine leads to significantly lower drug concentrations of quetiapine, probably via an induction of CYP3A4. Clinicians must consider the risk of adverse drug reactions, especially treatment failure under quetiapine when adding metamizole.
METHODS: Plasma concentrations of quetiapine from a large therapeutic drug monitoring database were analysed. Two groups of 33 patients, either receiving quetiapine as a monotherapy (without CYP modulating comedications) or with concomitantly applied metamizole, were compared addressing a potential impact of metamizole on the metabolism of quetiapine being reflected in differences of plasma concentrations of quetiapine and dose-adjusted plasma concentrations.
RESULTS: Patients comedicated with metamizole showed >50% lower plasma concentrations of quetiapine (median 45.2 ng/mL, Q1 = 15.5; Q3 = 90.5 vs. 92.0 ng/mL, Q1 = 52.3; Q3 = 203.8, P = .003). The dose-adjusted plasma concentrations were 69% lower in the comedication group (P = .001). Subgroup analyses did not suggest a dose dependency of the metamizole effect or an influence of quetiapine formulation (immediate vs. extended release). Finally, the comedication group exhibited a significantly higher proportion of patients whose quetiapine concentrations were below the therapeutic reference range (78.8% in the metamizole group vs. 54.4% in the control group, P = .037) indicating therapeutically insufficient drug concentrations.
CONCLUSIONS: The combination of metamizole and quetiapine leads to significantly lower drug concentrations of quetiapine, probably via an induction of CYP3A4. Clinicians must consider the risk of adverse drug reactions, especially treatment failure under quetiapine when adding metamizole.
摘要：
目的：安乃近是一种相当古老的镇痛药，解热和痉挛特性。最近的研究结果表明，它可以诱导几种细胞色素P450（CYP）酶，尤其是CYP3A4和CYP2B6。这些特性的临床相关性是不确定的。我们的目的是揭示安乃近和CYP3A4底物喹硫平之间潜在的药代动力学相互作用。
方法：分析了来自大型治疗药物监测数据库的喹硫平的血浆浓度。两组33例，要么接受喹硫平作为单一疗法（无CYP调节粉刺），要么同时应用安乃近，我们进行了比较，发现美乃唑对喹硫平代谢的潜在影响反映在喹硫平的血浆浓度和剂量调整后的血浆浓度的差异上。
结果：服用安乃近的患者显示喹硫平的血浆浓度降低>50％（中位数为45.2ng/mL，Q1=15.5；Q3=90.5vs.92.0ng/mL,Q1=52.3；Q3=203.8，P=.003）。剂量调整后的血浆浓度在昏迷组降低了69％（P=.001）。亚组分析未表明安乃近效应或喹硫平制剂的影响存在剂量依赖性（立即与延长释放)。最后,在喹硫平浓度低于治疗参考范围的患者中，昏迷组表现出明显更高的比例（安乃近组78.8%与对照组54.4%,P=0.037）表示治疗药物浓度不足。
结论：安乃近和喹硫平合用导致喹硫平的药物浓度明显降低，可能是通过CYP3A4的诱导。临床医生必须考虑药物不良反应的风险，特别是在喹硫平下加入安乃近时治疗失败。
方法：分析了来自大型治疗药物监测数据库的喹硫平的血浆浓度。两组33例，要么接受喹硫平作为单一疗法（无CYP调节粉刺），要么同时应用安乃近，我们进行了比较，发现美乃唑对喹硫平代谢的潜在影响反映在喹硫平的血浆浓度和剂量调整后的血浆浓度的差异上。
结果：服用安乃近的患者显示喹硫平的血浆浓度降低>50％（中位数为45.2ng/mL，Q1=15.5；Q3=90.5vs.92.0ng/mL,Q1=52.3；Q3=203.8，P=.003）。剂量调整后的血浆浓度在昏迷组降低了69％（P=.001）。亚组分析未表明安乃近效应或喹硫平制剂的影响存在剂量依赖性（立即与延长释放)。最后,在喹硫平浓度低于治疗参考范围的患者中，昏迷组表现出明显更高的比例（安乃近组78.8%与对照组54.4%,P=0.037）表示治疗药物浓度不足。
结论：安乃近和喹硫平合用导致喹硫平的药物浓度明显降低，可能是通过CYP3A4的诱导。临床医生必须考虑药物不良反应的风险，特别是在喹硫平下加入安乃近时治疗失败。
