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


CONCLUSIONS
The genetic variants in the MDR1 gene alone cannot explain the large variability in vincristine pharmacokinetics.
Plasschaert
Sabine L A
SL
Department of Pediatric Hematology and Oncology, University Hospital Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
Groninger
Ellis
E
Boezen
Marike
M
Kema
Ido
I
de Vries
Elisabeth G E
EG
Uges
Donald
D
Veerman
Anjo J P
AJ
Kamps
Willem A
WA
Vellenga
Edo
E
de Graaf
Siebold S
SS
de Bont
Eveline S J M
ES
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D005260:Female; D019450:Genes, MDR; D006239:Haplotypes; D006801:Humans; D007223:Infant; D008297:Male; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D012189:Retrospective Studies; D014750:Vincristine / Q000009:adverse effects / Q000493:pharmacokinetics*
D014750:Vincristine; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A