AMG 487-, M2-, and diltiazem-mediated microsomal CYP3A IC50 shift data
Values were determined in HLM by substrate addition or dilution methods, using midazolam or testosterone as reporter substrate.
| Inhibitor | Preincubation Time | Substrate | IC50 Shift by Substrate Addition | IC50 Shift by Dilution | ||||
|---|---|---|---|---|---|---|---|---|
| IC50 −NADPH | IC50 +NADPH | Shift | IC50 −NADPH | IC50 +NADPH | Shift | |||
| min | μM | μM | ||||||
| M2 | 30 | MDZ | N.D. | N.D. | 0.65 | 0.027 | 24 | |
| Test | N.D. | N.D. | 2.1 | 0.068 | 31 | |||
| AMG 487 | 30 | MDZ | 8.3 | 5.7 | 1.5 | 7.0 | 5.2 | 1.4 |
| Test | 20 | 22 | 0.9 | 26 | 25 | 1.1 | ||
| 90 | MDZ | 9.2 | 2.9 | 3.2 | 8.0 | 2.7 | 2.9 | |
| Test | 30 | 27 | 1.1 | 30 | 21 | 1.4 | ||
| Diltiazem | 30 | MDZ | 110 | 62 | 1.7 | 100 | 12 | 8.5 |
| Test | 80 | 36 | 2.2 | 190 | 8.1 | 23 | ||
| 90 | MDZ | 146 | 19 | 7.9 | 110 | 0.10 | 1200 | |
| Test | 220 | 9.6 | 23 | 220 | 0.10 | 2300 | ||
MDZ, midazolam; Test, testosterone; N.D., not determined.