Inhibition of the formation of irosustat metabolites in incubations with HLM in the presence of P450-selective chemical inhibitors
Results are expressed as percentage of inhibition relative to control incubations (without inhibitor) and are the mean values from duplicate incubations except for CYP2C19 which were triplicate incubations. Bold numbers represent >20% inhibition.
| Chemical Inhibitorsa | Inhibition | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| M7 | M8 | M9 | M11 | M13 | M14 | M16 | M18 | P-36 | |
| % | |||||||||
| CYP1A2 | −1.9 | −1.4 | 0.0 | −22.2 | −0.2 | 14.4 | −16.1 | −4.4 | −4.5 |
| CYP2A6 | 45.6 | 48.0 | 22.1 | 5.0 | N.Q. | N.Q. | 32.9 | 53.0 | 37.1 |
| CYP2B6 | 23.5 | 21.4 | 47.9 | 48.1 | 30.2 | 32.0 | 24.1 | 30.3 | 17.7 |
| CYP2C8 | 51.5 | 49.4 | 64.9 | 50.0 | 50.9 | 33.4 | 43.3 | 61.4 | 35.8 |
| CYP2C9 | 41.8 | 71.2 | 17.7 | 8.9 | 51.3 | −1.5 | 37.7 | 65.7 | 60.5 |
| CYP2C19 (a) | 10.0 | 19.6 | 13.8 | 17.3 | 14.0 | −24.8 | 9.4 | 19.8 | 10.9 |
| CYP2C19 (b) | −2.8 | −9.3 | −18.4 | −17.0 | −4.8 | −21.2 | −9.0 | 1.3 | −3.5 |
| CYP2D6 | 14.5 | N.Q. | N.Q. | N.Q. | 12.6 | 10.7 | 8.4 | 22.6 | 6.9 |
| CYP2E1 | 24.3 | 4.5 | 17.5 | 33.6 | 9.9 | 4.7 | 7.5 | 26.9 | 8.8 |
| CYP3A4/5 | 11.8 | 1.0 | 36.5 | 15.3 | 24.0 | 55.7 | 20.3 | 23.5 | −4.1 |
N.Q., not quantified because of HPLC coelution of the inhibitor with the metabolites.
↵a P450 inhibitors: 1 μM furafylline (CYP1A2); 0.1 μM methoxsalen (CYP2A6); 750 μM orphenadrine (CYP2B6); 10 μM quercetin (CYP2C8); 2 μM sulfaphenazole (CYP2C9); 100 μM nootkatone (a) and 5 μM (+)-N-3-benzyl-nirvanol (b) (CYP2C19); 0.5 μM quinidine (CYP2D6);15 μM 4-methylpyrazole (CYP2E1); and 0.5 μM ketoconazole (CYP3A4/5).