title: Influence of CYP2C8 polymorphisms on imatinib steady-state trough level in chronic myeloid leukemia and gastrointestinal stromal tumor patients.
abstract: Imatinib trough levels have been associated with its clinical effects. During chronic use of imatinib, CYP2C8 becomes an important metabolizing enzyme because of cytochrome P450 3A4 (CYP3A4) autoinhibition. Single nucleotide polymorphisms (SNPs) in CYP2C8 may affect imatinib trough levels. This study investigates the effect of common CYP2C8 polymorphisms [*1B (rs7909236), *1C (rs17110453), *3 (rs11572080 and rs10509681), and *4 (rs1058930)] on steady-state trough levels imatinib during chronic imatinib use in 43 patients with chronic myeloid leukemia or gastrointestinal stromal tumors. Standardized imatinib trough levels did not show a significant difference between wild-type and variant groups for any of the tested SNPs, but an association with age was found, with older patients having higher trough levels. This suggests that common CYP2C8 SNPs have no effect on the pharmacokinetics of imatinib.
authors.affiliation: Departments of aMedical Oncology bClinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden cCentral Hospital Pharmacy dDepartment of Hospital Pharmacy eDepartment of Hematology, Haga Teaching Hospital, The Hague fDepartment of Epidemiology, Erasmus MC - University Medical Center Rotterdam, Rotterdam gHospital Pharmacy hDepartment of Internal Medicine, Reinier de Graaf Group, Delft, The Netherlands.
authors.forename: Michiel C
authors.initials: MC
authors.lastname: Verboom
authors.forename: Loes
authors.initials: L
authors.lastname: Visser
authors.forename: Sander
authors.initials: S
authors.lastname: Kouwen
authors.forename: Jesse J
authors.initials: JJ
authors.lastname: Swen
authors.forename: Jeroen
authors.initials: J
authors.lastname: Diepstraten
authors.forename: Ward F
authors.initials: WF
authors.lastname: Posthuma
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
authors.forename: Daniëlle
authors.initials: D
authors.lastname: van Lammeren
authors.forename: Erik B
authors.initials: EB
authors.lastname: Wilms
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D065727:Cytochrome P-450 CYP2C8 / Q000235:genetics*; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D000071184:Pharmacogenomic Variants; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies
chemical_list: D000970:Antineoplastic Agents; D000068877:Imatinib Mesylate; C450259:CYP2C8 protein, human; D065727:Cytochrome P-450 CYP2C8