TY - JOUR
T1 - CYP2C8 Genotype Significantly Alters Imatinib Metabolism in Chronic Myeloid Leukaemia Patients
AU - Barratt, Daniel T.
AU - Cox, Hannah K.
AU - Menelaou, Andrew
AU - Yeung, David
AU - White, Deborah
AU - Hughes, Timothy
AU - Somogyi, Andrew A.
N1 - Publisher Copyright:
© 2016, Springer International Publishing Switzerland.
PY - 2017/8/1
Y1 - 2017/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85006489511&partnerID=8YFLogxK
U2 - 10.1007/s40262-016-0494-0
DO - 10.1007/s40262-016-0494-0
M3 - Article
C2 - 27995529
AN - SCOPUS:85006489511
SN - 0312-5963
VL - 56
SP - 977
EP - 985
JO - Clinical Pharmacokinetics
JF - Clinical Pharmacokinetics
IS - 8
ER -