Gréen Henrik, Khan Muhammad Suleman, Jakobsen-Falk Ingrid, Åvall-Lundqvist Elisabeth, Peterson Curt
Clinical Pharmacology, Division of Drug Research, Faculty of Health Sciences, Linköping University, SE-581 85 Linköping, Sweden; Science for Life Laboratory, School of Biotechnology, Division of Gene Technology, Royal Institute of Technology, SE-171 65 Solna, Sweden.
J Pharm Sci. 2011 Oct;100(10):4205-9. doi: 10.1002/jps.22680. Epub 2011 Jun 23.
The influence of genetic variants on paclitaxel-induced toxicity is of considerable interest for reducing adverse drug reactions. Recently, the genetic variants CYP2C83, CYP2C8-HapC, and CYP3A53 were associated with paclitaxel-induced neurotoxicity. We, therefore, investigated the impact of CYP2C8-HapC and CYP3A53 on paclitaxel/carboplatin-induced myelosuppression and neurotoxicity. Thirty-three patients from a prospective pharmacokinetics study were genotyped using pyrosequencing. Patients with variant alleles of CYP2C8-HapC were found to have significantly lower nadir values of both leukocytes and neutrophils (p < 0.05) than patients with the wild-type genotype. CYP3A53/*1 patients were shown to have borderline, significantly lower nadir values of leukocytes (p = 0.07) than *3/*3 patients. Combining the two genotypes resulted in a significant correlation with both leukopenia and neutropenia (p = 0.01). No effect of these genetic variants on neurotoxicity could be shown in this rather small study, but their importance for paclitaxel-induced toxicity could be confirmed.
基因变异对紫杉醇诱导毒性的影响在减少药物不良反应方面备受关注。最近，基因变异CYP2C83、CYP2C8-HapC和CYP3A53与紫杉醇诱导的神经毒性有关。因此，我们研究了CYP2C8-HapC和CYP3A53对紫杉醇/卡铂诱导的骨髓抑制和神经毒性的影响。使用焦磷酸测序对一项前瞻性药代动力学研究中的33名患者进行基因分型。发现携带CYP2C8-HapC变异等位基因的患者白细胞和中性粒细胞的最低点值均显著低于野生型基因型患者（p < 0.05）。CYP3A53/1患者白细胞最低点值略低于3/*3患者，差异接近显著（p = 0.07）。两种基因型组合与白细胞减少和中性粒细胞减少均存在显著相关性（p = 0.01）。在这项规模较小的研究中，未显示这些基因变异对神经毒性有影响，但它们对紫杉醇诱导毒性的重要性得到了证实。
