Inhibition of SLC transporter–dependent substrate uptake by MKI drugs
Data are presented as IC50 values or means ± S.D. of three individual reactions expressed as percentage of control (solvent alone).
| MKI | SLC Transportera | ||||||
|---|---|---|---|---|---|---|---|
| OATP1A2 (E3S)b | OATP1B1 (E3S) | OATP1B3 (CCK-8) | OATP2B1 (E3S) | OAT3 (E3S) | OCT1 (MPP+) | OCTN2 (L-Carnitine) | |
| Gefitinib | 0.88 | 105 ± 3 | 78 ± 3 | 0.65 | 66 ± 5*** | 57 ± 5*** | 92 ± 4 |
| Lapatinib | 72 ± 2*** | 123 ± 13 | 98 ± 16 | 84 ± 0.5** | 85 ± 7 | 96 ± 9 | 99 ± 8 |
| Nilotinib | 1.45 | 110 ± 7 | 100 ± 3 | 2.67 | 0.41 | 91 ± 1 | 99 ± 2 |
| Sunitinib | 2.03 | 109 ± 10 | 101 ± 10 | 88 ± 1 | 67 ± 3*** | 67 ± 7*** | 81 ± 6 |
| Bosutinib | 55 ± 3*** | 121 ± 6 | 109 ± 5 | 111 ± 3 | 81 ± 11 | 2.06 | 86 ± 10 |
| Vandetanib | 2.45 | 110 ± 6 | 71 ± 5*** | 82 ± 5*** | 75 ± 2** | 68 ± 1*** | 106 ± 6 |
| Afatinib | 1.17 | 119 ± 4 | 66 ± 3*** | 2.08 | 97 ± 0.4 | 80 ± 8*** | 98 ± 3 |
| Cediranib | 0.03 | 103 ± 5 | 64 ± 5*** | 79 ± 3*** | 73 ± 10** | 54 ± 2*** | 2.49 |
| Erlotinib | 1.10 | 104 ± 5 | 1.19 | 0.03 | 81 ± 2 | 86 ± 4* | 92 ± 3 |
| Pelitinib | 3.77 | 104 ± 4 | 66 ± 1*** | 2.01 | 82 ± 0.4 | 76 ± 1*** | 94 ± 5 |
| Neratinib | 0.39 | 110 ± 10 | 0.65 | 2.68 | 73 ± 2** | 77 ± 2*** | 92 ± 4 |
| Foretinib | 3.55 | 96 ± 7 | 68 ± 0.5*** | 54 ± 0.5*** | 63 ± 8*** | 74 ± 4*** | 91 ± 4 |
| Sorafenib | 90 ± 11 | 114 ± 0.1 | 109 ± 4 | 79 ± 1*** | 90 ± 11 | 99 ± 0.4 | 94 ± 8 |
| N′-Hydroxymethylsorafenib N-oxide | 64 ± 9** | 64 ± 9*** | 66 ± 4*** | 70 ± 1*** | 51 ± 5*** | 93 ± 0.4 | 89 ± 1 |
| Sorafenib N-oxide | 78 ± 6*** | 81 ± 1*** | 80 ± 3 | 66 ± 5*** | 79 ± 1 | 108 ± 2 | 87 ± 4 |
| N′-Hydroxymethylsorafenib | 85 ± 6 | 101 ± 4 | 113 ± 8 | 90 ± 4 | 73 ± 12** | 103 ± 5 | 96 ± 4 |
| N′-Desmethylsorafenib | 101 ± 5 | 59 ± 1*** | 130 ± 9 | 103 ± 5 | 81 ± 7 | 111 ± 0.4 | 108 ± 0.4 |
| N′-Desmethylsorafenib N-oxide | 91 ± 8 | 108 ± 2 | 96 ± 4 | 99 ± 8 | 61 ± 6*** | 109 ± 3 | 116 ± 4 |
↵a Fold increases in substrate uptake in SLC cDNA-transfected to untransfected cells (mean ± S.E.M., n = 3–8) were as follows: OATP1A2 (16.0 ± 0.01), OATP1B1 (23.5 ± 2), OATP1B3 (7.4 ± 0.7), OATP2B1 (5.0 ± 0.5), OAT1 (10.6 ± 0.2), OAT2 (1.9 ± 0.01), OAT3 (30.0 ± 1.2), OAT4 (7.6 ± 0.02), OCT1 (11.3 ± 0.05), OCT2 (10.0 ± 0.4), OCT3 (16.8 ± 0.04), OCTN1 (23.9 ± 0.2), and OCTN2 (20.8 ± 0.03).
↵b Transporter substrate.
Inhibition relative to control: *P < 0.05, **P < 0.01, ***P < 0.001.