CYP2C8 genotype significantly alters imatinib metabolism in chronic myeloid leukaemia patients
Date
2017
Authors
Barratt, D.
Cox, H.
Menelaou, A.
Yeung, D.
White, D.
Hughes, T.
Somogyi, A.
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Journal article
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Clinical Pharmacokinetics, 2017; 56(8):977-985
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Daniel T. Barratt, Hannah K. Cox, Andrew Menelaou, David T. Yeung, Deborah L. White, Timothy P. Hughes, Andrew A. Somogyi
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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.
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© Springer International Publishing Switzerland 2016.