From the Center for Psychopharmacology, Diakonhjemmet Hospital.
Department of Chronic Diseases and Ageing, Norwegian Institute of Public Health.
J Clin Psychopharmacol. 2022;42(5):470-474. doi: 10.1097/JCP.0000000000001585. Epub 2022 Aug 2.
PURPOSE/BACKGROUND: Pharmacokinetics may be of relevance for the risk of clozapine discontinuation. We compared metabolite profiles, accounting for smoking habits, in patients switching versus maintaining clozapine treatment at therapeutic concentrations.
METHODS/PROCEDURES: Adult patients with clozapine serum levels above 1070 nmol/L (350 ng/mL) were retrospectively included from a Norwegian therapeutic drug monitoring service during 2018-2020. Inclusion criteria were (1) known smoking habits, (2) blood sample drawn within 10 to 30 hours after last clozapine intake, and (3) detectable levels of N -desmethylclozapine, clozapine -N -oxide, clozapine-5 N -glucuronide, or clozapine- N + - glucuronide. Patients comedicated with cytochrome P450 enzyme inducers, inhibitors, or valproic acid were excluded. The high-resolution mass spectrometry assay enabled detection of 21 clozapine metabolites. Metabolite profiles were compared between patients switching treatment (switchers), measured as clozapine being replaced by another antipsychotic drug in blood samples, versus maintaining clozapine treatment (nonswitchers) during the study period.
FINDINGS/RESULTS: Of the 84 patients fulfilling the study criteria, 7 patients (8.3%) were identified as clozapine switchers. After correcting for smoking habits, the clozapine-5 N -glucuronide/clozapine ratio was 69% lower ( P < 0.001), while the clozapine- N + -glucuronide/clozapine-5 N -glucuronide ratio was 143% higher ( P = 0.026), respectively, in switchers versus nonswitchers. The other metabolite ratios did not significantly differ between switchers and nonswitchers.
IMPLICATIONS/CONCLUSIONS: The present study found a significantly reduced 5 N -glucuronidation phenotype in patients switching from clozapine at therapeutic serum concentrations (>1070 nmol/L) to other antipsychotic drugs. This may indicate that glucuronidation, as a potential detoxification mechanism, is related to clozapine tolerability. However, the causality of this observation needs to be investigated in future studies with larger patient populations.
目的/背景：药代动力学可能与氯氮平停药的风险有关。我们比较了在治疗浓度下转换和维持氯氮平治疗的患者的代谢产物谱，同时考虑了吸烟习惯。
方法/程序：从 2018 年至 2020 年，从挪威治疗药物监测服务中回顾性纳入氯氮平血清水平高于 1070nmol/L（350ng/mL）的成年患者。纳入标准为：（1）已知吸烟习惯，（2）在最后一次氯氮平摄入后 10 至 30 小时内抽取血样，以及（3）可检测到 N-去甲基氯氮平、氯氮平-N-氧化物、氯氮平-5 N-葡萄糖醛酸或氯氮平-N + -葡萄糖醛酸的水平。排除同时合用细胞色素 P450 酶诱导剂、抑制剂或丙戊酸的患者。高分辨率质谱分析可检测 21 种氯氮平代谢物。在研究期间，将治疗转换的患者（转换者）的代谢产物谱与维持氯氮平治疗的患者（非转换者）进行比较，定义为在血样中氯氮平被另一种抗精神病药物取代。
结果/发现：在符合研究标准的 84 名患者中，有 7 名（8.3%）患者被确定为氯氮平转换者。在校正吸烟习惯后，转换者的氯氮平-5 N-葡萄糖醛酸/氯氮平比值降低了 69%（P<0.001），而氯氮平-N + -葡萄糖醛酸/氯氮平-5 N-葡萄糖醛酸比值升高了 143%（P=0.026）。与非转换者相比，转换者的其他代谢物比值无显著差异。
意义/结论：本研究发现，在治疗血清浓度（>1070nmol/L）的氯氮平转换为其他抗精神病药物的患者中，5 N-葡萄糖醛酸化表型显著降低。这可能表明，葡萄糖醛酸化作为一种潜在的解毒机制，与氯氮平的耐受性有关。然而，这种观察结果的因果关系需要在未来更大的患者人群研究中进行调查。
