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https://hdl.handle.net/2440/116605
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Type: | Journal article |
Title: | CYP2C8 genotype significantly alters imatinib metabolism in chronic myeloid leukaemia patients |
Author: | Barratt, D. Cox, H. Menelaou, A. Yeung, D. White, D. Hughes, T. Somogyi, A. |
Citation: | Clinical Pharmacokinetics, 2017; 56(8):977-985 |
Publisher: | Springer |
Issue Date: | 2017 |
ISSN: | 0312-5963 1179-1926 |
Statement of Responsibility: | Daniel T. Barratt, Hannah K. Cox, Andrew Menelaou, David T. Yeung, Deborah L. White, Timothy P. Hughes, Andrew A. Somogyi |
Abstract: | Objective: The aims of this study were to determine the effects of the CYP2C8*3 and *4 polymorphisms on imatinib metabolism and plasma imatinib concentrations in chronic myeloid leukaemia (CML) patients. Methods: We genotyped 210 CML patients from the TIDELII trial receiving imatinib 400–800 mg/day for CYP2C8*3 (rs11572080, rs10509681) and *4 (rs1058930). Steady-state trough total plasma N-desmethyl imatinib (major metabolite):imatinib concentration ratios (metabolic ratios) and trough total plasma imatinib concentrations were compared between genotypes (one-way ANOVA with Tukey post hoc). Results: CYP2C8*3 (n = 34) and *4 (n = 15) carriers had significantly higher (P < 0.01) and lower (P < 0.01) metabolic ratios, respectively, than CYP2C8*1/*1 (n = 147) patients (median ± standard deviation: 0.28 ± 0.08, 0.18 ± 0.06 and 0.22 ± 0.08, respectively). Plasma imatinib concentrations were consequently > 50% higher for CYP2C8*1/*4 than for CYP2C8*1/*1 and CYP2C8*3 carriers (2.18 ± 0.66 vs. 1.45 ± 0.74 [P < 0.05] and 1.36 ± 0.98 μg/mL [P < 0.05], respectively). Conclusions: CYP2C8 genotype significantly alters imatinib metabolism in patients through gain- and loss-of-function mechanisms. |
Keywords: | Imatinib; human liver microsome; chronic myeloid leukaemia patient; metabolic ratio; systemic mastocytosis |
Rights: | © Springer International Publishing Switzerland 2016. |
DOI: | 10.1007/s40262-016-0494-0 |
Published version: | http://dx.doi.org/10.1007/s40262-016-0494-0 |
Appears in Collections: | Aurora harvest 3 Medicine publications |
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