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Clin Pharmacol Ther. 2004 Sep;76(3):220-9.

Influence of functional polymorphisms of the MDR1 gene on vincristine pharmacokinetics in childhood acute lymphoblastic leukemia.

Author information

  • 1Department of Pediatric Hematology and Oncology, University Hospital Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.

Abstract

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.

PMID:
15371983
[PubMed - indexed for MEDLINE]
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