Center for Psychopharmacology, Diakonhjemmet Hospital, Oslo, Norway.
NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Br J Clin Pharmacol. 2024 Mar;90(3):740-747. doi: 10.1111/bcp.15721. Epub 2023 Apr 11.
The extensive variability in cytochrome P450 2D6 (CYP2D6) metabolism is mainly caused by genetic polymorphisms. However, there is large, unexplained variability in CYP2D6 metabolism within CYP2D6 genotype subgroups. Solanidine, a dietary compound found in potatoes, is a promising phenotype biomarker predicting individual CYP2D6 metabolism. The aim of this study was to investigate the correlation between solanidine metabolism and the CYP2D6-mediated metabolism of risperidone in patients with known CYP2D6 genotypes.
The study included therapeutic drug monitoring (TDM) data from CYP2D6-genotyped patients treated with risperidone. Risperidone and 9-hydroxyrisperidone levels were determined during TDM, and reprocessing of the respective TDM full-scan high-resolution mass spectrometry files was applied for semi-quantitative measurements of solanidine and five metabolites (M402, M414, M416, M440 and M444). Spearman's tests determined the correlations between solanidine metabolic ratios (MRs) and the 9-hydroxyrisperidone-to-risperidone ratio.
A total of 229 patients were included. Highly significant, positive correlationswere observed between all solanidine MRs and the 9-hydroxyrisperidone-to-risperidone ratio (ρ > 0.6, P < .0001). The strongest correlation was observed for the M444-to-solanidine MR in patients with functional CYP2D6 metabolism, i.e., genotype activity scores of 1 and 1.5 (ρ 0.72-0.77, P < .0001).
The present study shows strong, positive correlations between solanidine metabolism and CYP2D6-mediated risperidone metabolism. The strong correlation within patients carrying CYP2D6 genotypes encoding functional CYP2D6 metabolism suggests that solanidine metabolism may predict individual CYP2D6 metabolism, and hence potentially improve personalized dosing of drugs metabolized by CYP2D6.
细胞色素 P450 2D6（CYP2D6）代谢的广泛变异性主要是由遗传多态性引起的。然而，在 CYP2D6 基因型亚组中，CYP2D6 代谢存在很大且无法解释的变异性。茄碱是一种存在于土豆中的膳食化合物，是预测个体 CYP2D6 代谢的有前途的表型生物标志物。本研究旨在调查已知 CYP2D6 基因型患者中茄碱代谢与 risperidone 的 CYP2D6 介导代谢之间的相关性。
本研究包括接受 risperidone 治疗的 CYP2D6 基因分型患者的治疗药物监测（TDM）数据。在 TDM 期间测定了 risperidone 和 9-羟基 risperidone 的水平，并对各自的 TDM 全扫描高分辨率质谱文件进行了重新处理，用于半定量测定茄碱和五种代谢物（M402、M414、M416、M440 和 M444）。Spearman 检验确定了茄碱代谢比（MR）与 9-羟基 risperidone 与 risperidone 比值之间的相关性。
共纳入 229 例患者。所有茄碱 MR 与 9-羟基 risperidone 与 risperidone 比值之间均存在高度显著的正相关（ρ>0.6，P<.0001）。在功能 CYP2D6 代谢患者中，即基因型活性评分 1 和 1.5 的患者中，观察到 M444 与茄碱 MR 之间的相关性最强（ρ 0.72-0.77，P<.0001）。
本研究表明茄碱代谢与 CYP2D6 介导的 risperidone 代谢之间存在强烈的正相关。在携带编码功能 CYP2D6 代谢的 CYP2D6 基因型的患者中，这种强烈的相关性表明茄碱代谢可能预测个体 CYP2D6 代谢，从而可能改善 CYP2D6 代谢的药物的个体化给药。
