Daniel T Barratt1,2, Hannah K Cox3, Andrew Menelaou4, David T Yeung4,5,6, Deborah L White4,6, Timothy P Hughes4,5,6, Andrew A Somogyi3,7,8. 1. Discipline of Pharmacology, Adelaide Medical School, University of Adelaide, Adelaide, SA, 5005, Australia. daniel.barratt@adelaide.edu.au. 2. Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia. daniel.barratt@adelaide.edu.au. 3. Discipline of Pharmacology, Adelaide Medical School, University of Adelaide, Adelaide, SA, 5005, Australia. 4. South Australian Health and Medical Research Institute (SAHMRI), Adelaide, SA, Australia. 5. Department of Haematology, SA Pathology, Adelaide, SA, Australia. 6. Adelaide Medical School, University of Adelaide, Adelaide, SA, Australia. 7. Centre for Personalised Cancer Medicine, University of Adelaide, Adelaide, SA, Australia. 8. Department of Clinical Pharmacology, Royal Adelaide Hospital, Adelaide, SA, Australia.
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.
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 CMLpatients 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.
Authors: H Schmidli; B Peng; G-J Riviere; R Capdeville; M Hensley; I Gathmann; A E Bolton; A Racine-Poon Journal: Br J Clin Pharmacol Date: 2005-07 Impact factor: 4.335
Authors: A Di Paolo; M Polillo; M Capecchi; G Cervetti; C Baratè; S Angelini; F Guerrini; G Fontanelli; R Arici; E Ciabatti; S Grassi; G Bocci; P Hrelia; R Danesi; M Petrini; S Galimberti Journal: Pharmacogenomics J Date: 2014-03-04 Impact factor: 3.550
Authors: Goncalo R Abecasis; Adam Auton; Lisa D Brooks; Mark A DePristo; Richard M Durbin; Robert E Handsaker; Hyun Min Kang; Gabor T Marth; Gil A McVean Journal: Nature Date: 2012-11-01 Impact factor: 49.962
Authors: Päivi Hirvensalo; Aleksi Tornio; Mikko Neuvonen; Tuija Tapaninen; Maria Paile-Hyvärinen; Vesa Kärjä; Ville T Männistö; Jussi Pihlajamäki; Janne T Backman; Mikko Niemi Journal: Clin Pharmacol Ther Date: 2017-11-06 Impact factor: 6.875
Authors: Yi-Han Chien; Gudrun Würthwein; Pablo Zubiaur; Bianca Posocco; María Ángeles Pena; Alberto M Borobia; Sara Gagno; Francisco Abad-Santos; Georg Hempel Journal: Cancer Chemother Pharmacol Date: 2022-07-14 Impact factor: 3.288