Reversible inhibition of CYP1A2, CYP2C9, CYP2D6, and CYP3A4 activities in HLM by AMIO and its circulating human metabolites
IC50 values are the mean, with S.E. measurements, determined from (at least) duplicate experiments.
| Inhibitor | CYP1A2a | CYP2C9b | CYP2D6c | CYP3A4d | ||||
|---|---|---|---|---|---|---|---|---|
| IC50 | [I]u/Ki,u | IC50 | [I]u/Ki,u | IC50 | [I]u/Ki,u | IC50 | [I]u/Ki,u | |
| μM | μM | μM | μM | |||||
| AMIO | >50 | <0.1 | >50 | <0.1 | 15 ± 9.5 | 0.34 | >50 | <0.1 |
| MDEA | >100 | <0.07 | 57 ± 9 | 0.07 | 17 ± 2.1 | 0.23 | 43 ± 5 | 0.09 |
| DDEA | 1.6 ± 0.42 | 0.28 | 0.64 ± 0.01 | 0.71 | 9.6 ± 2.8 | 0.05 | 1.8 ± 0.9 | 0.25 |
| OH-MDEA | >100 | <0.001 | 3.3 ± 1.4 | 0.03 | 5.3 ± 2.3 | 0.02 | 24 ± 0.7 | 0.01 |
| ODAA | >10 | <0.001 | 0.080 ± 0.034 | 0.08 | >10 | <0.001 | 8.6 ± 2.8 | 0.001 |
| DAA | >50 | <0.002 | >10 | <0.01 | >10 | <0.01 | >50 | <0.002 |
DAA, deaminated-amiodarone; ODAA, O-desalkylamiodarone; OH-MDEA, 3′-hydroxy-N-monodesethylamiodarone.
↵a Phenacetin O-dealkylation was used as a probe for CYP1A2 activity in HLM.
↵b Diclofenac 4′-hydroxylation was used as a probe for CYP2C9 activity in HLM.
↵c Dextromethorphan O-dealkylation was used as a probe for CYP2D6 activity in HLM.
↵d Midazolam 1′-hydroxylation was used as a probe for CYP3A4 activity in HLM.