Clozapine is an atypical antipsychotic metabolized by CYP1A2, CYP2D6, and CYP2C19 enzymes. Among 66 adult schizophrenia patients treated with clozapine-based combination therapies, we explored the impact of genotype-predicted CYP1A2, CYP2D6, and CYP2C19 activity on dose-adjusted clozapine concentrations and symptom severity, with and without correction for inhibitors and inducers of these enzymes. Uncorrected activity scores were not associated with dose-adjusted clozapine concentrations or symptom severity. CYP1A2 and CYP2D6 activity scores corrected for known inducers (i.e., smoking) and inhibitors (e.g., concomitant medications) were associated with dose-adjusted clozapine levels and in the case of CYP1A2, symptom severity. However, smoking status and certain inhibitors of clozapine metabolism (i.e., esomeprazole) explained significantly more variance in dose-adjusted clozapine levels relative to corrected activity scores. These findings highlight the clinical importance of nongenetic factors (smoking, concomitant medications) and suggest that the added utility of CYP1A2, CYP2D6, and CYP2C19 activity scores to guide clozapine dosing is currently limited.

氯氮平是一种通过CYP1A2，CYP2D6和CYP2C19酶代谢的非典型抗精神病药。在基于氯氮平的联合疗法治疗的66位成人精神分裂症患者中，我们探讨了基因型预测的CYP1A2，CYP2D6和CYP2C19活性对剂量调整的氯氮平浓度和症状严重程度的影响，以及是否校正了这些酶的抑制剂和诱导剂。未经校正的活动评分与剂量调整的氯氮平浓度或症状严重程度无关。CYP1A2和CYP2D6对已知诱导物（即吸烟）和抑制剂（例如，伴随药物）校正的活性评分与剂量调整的氯氮平水平相关，在CYP1A2的情况下，与症状严重程度相关。但是，吸烟状况和氯氮平代谢的某些抑制剂（例如，埃索美拉唑）说明，相对于校正后的活动评分，剂量调整后的氯氮平水平差异更大。这些发现突出了非遗传因素（吸烟，伴随用药）的临床重要性，并提示目前限制CYP1A2，CYP2D6和CYP2C19活性评分用于指导氯氮平用药的附加效用是有限的。