CYP2C8 Genotype Significantly Alters Imatinib Metabolism in Chronic Myeloid Leukaemia Patients

被引：25

作者：

Barratt, Daniel T. ^{[1
,2
]}

Cox, Hannah K. ^{[1
]}

Menelaou, Andrew ^{[3
]}

Yeung, David T. ^{[3
,4
,5
]}

White, Deborah L. ^{[3
,5
]}

Hughes, Timothy P. ^{[3
,4
,5
]}

Somogyi, Andrew A. ^{[1
,2
,6
]}

机构：

[1] Univ Adelaide, Adelaide Med Sch, Discipline Pharmacol, Adelaide, SA 5005, Australia

[2] Univ Adelaide, Ctr Personalised Canc Med, Adelaide, SA, Australia

[3] SAHMRI, Adelaide, SA, Australia

[4] SA Pathol, Dept Haematol, Adelaide, SA, Australia

[5] Univ Adelaide, Adelaide Med Sch, Adelaide, SA, Australia

[6] Royal Adelaide Hosp, Dept Clin Pharmacol, Adelaide, SA, Australia

来源：

CLINICAL PHARMACOKINETICS | 2017年 / 56卷 / 08期

关键词：

TYROSINE KINASE INHIBITORS; POPULATION PHARMACOKINETICS; TRANSPORTER POLYMORPHISMS; CLINICAL PHARMACOKINETICS; GENETIC POLYMORPHISMS; N-DEMETHYLATION; P-GLYCOPROTEIN; IN-VITRO; CYP3A4; ABCB1;

D O I：

10.1007/s40262-016-0494-0

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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 +/- A 0.08, 0.18 +/- A 0.06 and 0.22 +/- A 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 mu g/mL [P < 0.05], respectively). Conclusions CYP2C8 genotype significantly alters imatinib metabolism in patients through gain- and loss-of-function mechanisms.

引用

页码：977 / 985

页数：9

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