IC50 values for P450 and UGT inhibition with phosphodiester or phosphorothioate oligonucleotides in HLMs
| Enzyme | Substrate | IC50 | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| PD-GP | PT-GP | PD-Ac | PT-Ac | ||||||||||
| Direct | TDI | MDI | Direct | TDI | MDI | Direct | TDI | MDI | Direct | TDI | MDI | ||
| μM | |||||||||||||
| CYP1A2 | Phenacetin | >100 | >100 | >100 | 0.8 | 0.8 | 1.8 | >100 | >100 | >100 | 4.2 | 3.4 | 7.3 |
| CYP2B6 | Bupropion | >100 | >100 | >100 | 15 | 15 | 13 | >100 | >100 | >100 | 39 | 20 | 22 |
| CYP2C8 | Amodiaquine | >100 | >100 | >100 | 1.1 | 0.6 | 0.6 | >100 | >100 | >100 | 12 | 8.3 | 3.7 |
| CYP2C9 | Diclofenac | >100 | >100 | >100 | 97 | 36 | 47 | >100 | >100 | >100 | >100 | 53 | 57 |
| CYP2C19 | S-Mephenytoin | >100 | >100 | >100 | 21 | 8.7 | 19 | 29 | 36 | >100 | 80 | 39 | 98 |
| CYP2D6 | Dextromethorphan | >100 | >100 | >100 | 81 | 41 | >100 | >100 | >100 | >100 | >100 | 52 | >100 |
| CYP3A4/5 | Midazolam | >100 | >100 | >100 | >100 | 38 | 28 | >100 | >100 | >100 | >100 | 66 | 63 |
| UGT1A1 | Estradiol | >100 | NDa | ND | 4.5 | ND | ND | >100 | ND | ND | 5.4 | ND | ND |
| UGT1A3 | Chenodeoxycholic acid | >100 | ND | ND | 51 | ND | ND | >100 | ND | ND | 48 | ND | ND |
| UGT1A4 | Trifluoperazine | >100 | ND | ND | >100 | ND | ND | >100 | ND | ND | >100 | ND | ND |
| UGT1A6 | 1-Naphthol | >100 | ND | ND | 52 | ND | ND | >100 | ND | ND | 55 | ND | ND |
| UGT1A9 | Propofol | >100 | ND | ND | 19 | ND | ND | >100 | ND | ND | 42 | ND | ND |
| UGT2B7 | Morphine | >100 | ND | ND | >100 | ND | ND | >100 | ND | ND | >100 | ND | ND |
| UGT2B10 | Levomedetomidine | >100 | ND | ND | 26 | ND | ND | >100 | ND | ND | 41 | ND | ND |
| UGT2B15 | S-Oxazepam | >100 | ND | ND | 38 | ND | ND | >100 | ND | ND | 45 | ND | ND |
| UGT2B17 | Testosterone | >100 | ND | ND | 7.2 | ND | ND | >100 | ND | ND | 18 | ND | ND |
↵a ND indicates not done. The evaluation of TDI for UGT enzymes was performed at 30 μM oligonucleotide only as shown in Supplemental Fig. 2.