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Cytochrome P450 Genetic Variations Can Predict mRNA Expression, Cyclophosphamide 4‐Hydroxylation, and Treatment Outcomes in Chinese Patients With Non‐Hodgkin's Lymphoma
Author(s) -
Shu Wenying,
Chen Lingyan,
Hu Xiaoye,
Zhang Meimei,
Chen Wensheng,
Ma Lei,
Liu Xiaoyan,
Huang Jianing,
Pang Tingyuan,
Li Jia,
Zhang Yu
Publication year - 2017
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.878
Subject(s) - cyp2b6 , pharmacology , cyp2c19 , pharmacokinetics , medicine , cyp3a5 , cytochrome p450 , cyp3a4 , chemistry , gene , metabolism , genotype , biochemistry
Abstract To investigate the impact of cytochrome P450 (CYP) genetic polymorphisms CYP2B6 , CYP2C19 , and CYP3A5 on mRNA expression, cyclophosphamide/4‐hydroxycyclophosphamide pharmacokinetics, and treatment outcomes of the R‐CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in Chinese patients with non‐Hodgkin's lymphoma, 567 cases were investigated. Plasma concentrations of cyclophosphamide/4‐hydroxycyclophosphamide were determined using liquid chromatography–tandem mass spectrometry and pharmacokinetic parameters calculated. The frequencies of CYP2B6*1/*29 and CYP2B6*1/*30 were 18 (3.2%) and 30 (5.3%), respectively. Liver samples with CYP2B6*29/*30 , CYP2C19*2 , CYP2B6*6 , or CYP3A5*3 had significantly lower target mRNA expression. Samples with CYP2B6*6 and/or CYP2C19*2 had lower exposure to 4‐hydroxycyclophosphamide, whereas those with CYP2B6*1G/*1H had higher exposure. Multivariate model showed that samples with CYP2C19*2 or CYP2B6 785A>raG had worse treatment response than samples with CYP3A5*3 . CYP2C19*2 , CYP2B6*6 , CYP2B6*29 , and CYP2B6*30 were protective factors for toxicity in the multivariate model. The best model for gene–gene interactions for treatment response contained CYP2C19*2 , CYP2B6 785A>G , and CYP3A5*3 (cross‐validation consistency [CVC], 8/10; P = .0035). The best prediction model for grade 2–4 toxicities had CYP2C19*2 , CYP2B6 785A>G , and 516 G>T (CVC, 10/10; P < .0001). In previous reports, we were the first to report that the frequency of copy‐number variations in CYP2B6 is higher among Chinese than among other ethnic populations. Genetic variations in CYP2B6 , CYP2C19 , and CYP3A5 dramatically affected the mRNA expression of proteins, the pharmacokinetics of 4‐hydroxycyclophosphamide, and the R‐CHOP treatment response in Chinese subjects. Patients carrying CYP3A5*3 were more likely to have a better treatment response, whereas patients with CYP2C19*2 or CYP2B6 516G>T , or CYP2B6 785A>G had higher tolerance to treatment.