OBJECTIVE: Our objective was to investigate the effect of single nucleotide polymorphisms (SNPs) in the P-glycoprotein MDR1 gene on vincristine pharmacokinetics and side effects in childhood acute lymphoblastic leukemia. METHODS: From 52 of 70 children who participated in a previous study on vincristine pharmacokinetics, patient material was available for investigation of the MDR1 genetic variants. The SNPs C3435T and G2677T were determined by use of polymerase chain reaction-restriction fragment length polymorphism. Vincristine side effects were scored retrospectively from patient records. RESULTS: No association was observed between C3435T or G2677T and vincristine pharmacokinetic variables. When haplotypes were assigned, haplotype 1/1 carriers (3435C/2677G) showed a longer elimination half-life than noncarriers (1156 versus 805 minutes, P =.038). In contrast, haplotype 1/2 carriers (3435T/2677G) had a shorter elimination half-life than noncarriers (805 versus 1180 minutes, P =.044). However, this significance was lost after Bonferroni correction for multiple testing. The haplotypes did not affect the other pharmacokinetic parameters, such as clearance and area under the concentration-time curve, suggesting that the observed effect on elimination half-life is of very limited relevance. Moreover, SNPs in the MDR1 gene did not identify patients with an increased risk for vincristine-induced constipation. CONCLUSION: The genetic variants in the MDR1 gene alone cannot explain the large variability in vincristine pharmacokinetics.
OBJECTIVE: Our objective was to investigate the effect of single nucleotide polymorphisms (SNPs) in the P-glycoproteinMDR1 gene on vincristine pharmacokinetics and side effects in childhood acute lymphoblastic leukemia. METHODS: From 52 of 70 children who participated in a previous study on vincristine pharmacokinetics, patient material was available for investigation of the MDR1 genetic variants. The SNPs C3435T and G2677T were determined by use of polymerase chain reaction-restriction fragment length polymorphism. Vincristine side effects were scored retrospectively from patient records. RESULTS: No association was observed between C3435T or G2677T and vincristine pharmacokinetic variables. When haplotypes were assigned, haplotype 1/1 carriers (3435C/2677G) showed a longer elimination half-life than noncarriers (1156 versus 805 minutes, P =.038). In contrast, haplotype 1/2 carriers (3435T/2677G) had a shorter elimination half-life than noncarriers (805 versus 1180 minutes, P =.044). However, this significance was lost after Bonferroni correction for multiple testing. The haplotypes did not affect the other pharmacokinetic parameters, such as clearance and area under the concentration-time curve, suggesting that the observed effect on elimination half-life is of very limited relevance. Moreover, SNPs in the MDR1 gene did not identify patients with an increased risk for vincristine-induced constipation. CONCLUSION: The genetic variants in the MDR1 gene alone cannot explain the large variability in vincristine pharmacokinetics.
Authors: Barthelemy Diouf; Kristine R Crews; Glen Lew; Deqing Pei; Cheng Cheng; Ju Bao; Jie J Zheng; Wenjian Yang; Yiping Fan; Heather E Wheeler; Claudia Wing; Shannon M Delaney; Masaaki Komatsu; Steven W Paugh; Joseph Robert McCorkle; Xiaomin Lu; Naomi J Winick; William L Carroll; Mignon L Loh; Stephen P Hunger; Meenakshi Devidas; Ching-Hon Pui; M Eileen Dolan; Mary V Relling; William E Evans Journal: JAMA Date: 2015-02-24 Impact factor: 56.272
Authors: Lin Mei; Evelena P Ontiveros; Elizabeth A Griffiths; James E Thompson; Eunice S Wang; Meir Wetzler Journal: Blood Rev Date: 2015-01-10 Impact factor: 8.250
Authors: Jun J Yang; Cheng Cheng; Wenjian Yang; Deqing Pei; Xueyuan Cao; Yiping Fan; Stanley B Pounds; Geoffrey Neale; Lisa R Treviño; Deborah French; Dario Campana; James R Downing; William E Evans; Ching-Hon Pui; Meenakshi Devidas; W P Bowman; Bruce M Camitta; Cheryl L Willman; Stella M Davies; Michael J Borowitz; William L Carroll; Stephen P Hunger; Mary V Relling Journal: JAMA Date: 2009-01-28 Impact factor: 56.272