Imatinib disposition and ABCB1 (MDR1, P-glycoprotein) genotype.
The aim of this study was to explore the impact of individual variation in drug elimination on imatinib disposition. Twenty-two patients with gastrointestinal stromal tumor or chronic myeloid leukemia initially received imatinib 600 mg daily with dosage subsequently toxicity adjusted. Pharmacokinetic parameters on day 1 and at steady-state were compared with elimination phenotype and single-nucleotide polymorphisms of CYP3A5 and ABCB1. A fivefold variation in estimated imatinib clearance (CL/F) was present on day 1 and mean CL/F had fallen by 26% at steady state. This reduction in imatinib CL/F was associated with ABCB1 genotype, being least apparent in thymidine homozygotes at the 1236T>C, 2677G>T/A and 3435C>T loci. Toxicity-related dose reduction also tended to be less common in these individuals. ABCB1 genotype was associated with steady-state CL/F due to an apparent genotype-specific influence of imatinib on elimination. Further evaluation of ABCB1 genotype and imatinib dosage is warranted.
Gurney
H
H
Department of Medical Oncology, Westmead Hospital Sydney West Area Health Service, Westmead, New South Wales, Australia. howard_gurney@wmi.usyd.edu.au
Wong
M
M
Balleine
R L
RL
Rivory
L P
LP
McLachlan
A J
AJ
Hoskins
J M
JM
Wilcken
N
N
Clarke
C L
CL
Mann
G J
GJ
Collins
M
M
Delforce
S-E
SE
Lynch
K
K
Schran
H
H
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D001549:Benzamides; D015331:Cohort Studies; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D016903:Drug Monitoring; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D020641:Polymorphism, Single Nucleotide; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001549:Benzamides; D027361:Organic Anion Transporters; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D003577:Cytochrome P-450 Enzyme System; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A