Table 2.
Polymorphisms in phase I and phase II metabolic enzymes affecting pharmacokinetics of anticancer drugs
| Drugs | Gene | Mutations | dbSNP ID | ESP MAF | ExAC MAF | PK parameters | |
|---|---|---|---|---|---|---|---|
| African American | European American | ||||||
| Erlotinib | CYP1A2 | c.1042+43G>A | rs2472304 | 0.13 | 0.56 | 0.46 | Plasma concentrations [11] |
| Tegafur | CYP2A6 | CYP2A6*1A | Increased 5-FU formation [178] | ||||
| CYP2A6*4A | del | Decreased 5-FU formation [178] | |||||
| CYP2A6*4A-H | del | CL, AUC [13, 14] | |||||
| CYP2A6*7 (c.1412T>C) | rs5031016 | nr | 9 × 10−4 | 1.1 × 10−2 | CL, AUC [13, 14] | ||
| CYP2A6*9 (c.-48T>G) | rs28399433 | 0.08 | 0.06 | 0.10 | CL, AUC [13, 14, 178] | ||
| Cyclofosfamide | CYP2B6 | CYP2B6*6 | CL [15–18, 32] | ||||
| (c.516G>T) | rs3745274 | 0.37 | 0.25 | 0.27 | |||
| (c.785A>G) | rs2279343 | nr | nr | 0.06 | |||
| Busulfan | CYP2C9 | CYP2C9*2 (c.430C>T) | rs1799853 | 0.03 | 0.13 | 0.09 | Decreased CL [19] |
| Cyclophosphamide | CYP2C19 | CYP2C19*2 (c.681G>A) | rs4244285 | 0.17 | 0.15 | 0.19 | Reduced CL [16, 20, 179, 180] |
| CYP2C19*3 (c.636G>A) | rs4986893 | 5 × 10−4 | 2 × 10−4 | 6 × 10−3 | |||
| Gefitinib Tamoxifen |
CYP2D6 | CYP2D6*2xN | duplication | Endoxifen plasma concentrations [21–23, 28] | |||
| CYP2D6*3 (c.775delA) | rs35742686 | 4.5 × 10−3 | 1.7 × 10−2 | 1.3 × 10−2 | Gefitinib plasma concentrations [29, 30] | ||
| CYP2D6*4 (c.506-1G>A) | rs3892097 | 0.07 | 0.19 | 0.17 | |||
| CYP2D6*5 | del | ||||||
| CYP2D6*6 (c.454delT) | rs5030655 | 2 × 10−3 | 9 × 10−3 | 7.9 × 10−3 | |||
| CYP2D6*9 (c.841_843del) | rs5030656 | 5.9 × 10−3 | 2.7 × 10−2 | 1.9 × 10−2 | |||
| CYP2D6*10 (c.100C>T) | rs1065852 | 0.12 | 0.22 | 0.25 | |||
| CYP2D6*17 (c.320C>T) | rs28371706 | 0.17 | 1.8 × 10−2 | 1.8 × 10−2 | |||
| (c.886C>T) | rs16947 | 0.49 | 0.34 | 0.34 | |||
| Busulfan Chloorambucil Melphalan |
GSTA1 | GSTA1*B (c.-135T>C) | rs3957357 | nr | nr | nr | Reduced CL busulfan [32, 33] |
| Thiotepa | GSTP1 | GSTP1 (c.341C>T) | rs1138272 | 0.02 | 0.08 | 0.06 | Reduced CL thiotepa and tepa [34] |
| Irinotecan | UGT1A1 | UGT1A1*6 (c.211G>A) | rs4148323 | 0.01 | 0.01 | 0.02 | Reduced CL SN-38 [36–38, 42] |
| UGT1A1*28a | rs8175347 | ||||||
AUC area under the curve, CL clearance, ExAc Exome Aggregation Consortium, ESP Exome Sequencing Project, MAF minor allele frequency, nr not reported, PK pharmacokinetic, 5-FU 5-fluorouracil
aUGT1A1*28 occurs with a frequency of 0.26–0.31 in Caucasians, 0.42–0.56 in African Americans, and only 0.09–0.16 in Asian populations [181]