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19.12.2016 | Original Research Article

CYP2C8 Genotype Significantly Alters Imatinib Metabolism in Chronic Myeloid Leukaemia Patients

verfasst von: Daniel T. Barratt, Hannah K. Cox, Andrew Menelaou, David T. Yeung, Deborah L. White, Timothy P. Hughes, Andrew A. Somogyi

Erschienen in: Clinical Pharmacokinetics | Ausgabe 8/2017

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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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Titel: CYP2C8 Genotype Significantly Alters Imatinib Metabolism in Chronic Myeloid Leukaemia Patients
verfasst von: Daniel T. Barratt
Hannah K. Cox
Andrew Menelaou
David T. Yeung
Deborah L. White
Timothy P. Hughes
Andrew A. Somogyi
Publikationsdatum: 19.12.2016
Verlag: Springer International Publishing
Erschienen in: Clinical Pharmacokinetics / Ausgabe 8/2017
Print ISSN: 0312-5963
Elektronische ISSN: 1179-1926
DOI: https://doi.org/10.1007/s40262-016-0494-0

Springer Medizin

Abstract

Objective

Methods

Results

Conclusions

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