Abbreviations:7-OBz (7-benzoyl), CYP and P450 (cytochrome P450), EI (enzyme inhibitor), OH (hydroxyl), pmol (picomole), POR (NADPH–P450 reductase), SVD (singular value decomposition), UPLC (ultraperformance liquid chromatography)
- Shimada T.
- Yamazaki H.
- Mimura M.
- Inui Y.
- Guengerich F.P.
- Cheong E.J.Y.
- Nair P.C.
- Neo R.W.Y.
- Tu H.T.
- Lin F.
- Chiong E.
- Esuvaranathan K.
- Fan H.
- Szmulewitz R.Z.
- Peer C.J.
- Figg W.D.
- Chai C.L.L.
- Miners J.O.
- Chan E.C.Y.
Binding of 7-OBz quinoline to P450 3A4 and O-debenzylation
Inhibition of P450 3A4
Kinetics of recovery of P450 3A4–inhibitor complexes
Pre–steady-state kinetics of P450 3A4 inhibition
|Inhibitor||Onset of 7-OBz quinoline O-debenzylation inhibition|
|Spectral binding (SVD)|
|Concentration, μM||Rate (k1), s−1|
|t1/2, s||Concentration, μM||k1, s||k2, s−1|
|Ketoconazole||0.06||0.14 ± 0.01||4.8||15||0.38 ± 0.06||0.32 ±0.07|
|0.2||0.87 ± 0.21||0.8|
|Clotrimazole||0.02||0.39 ± 0.03||1.8||15||0.092 ± 0.01||0.016 ± 0.005|
|Ritonavir||0.02||0.028 ± 0.001||24||15||0.34 ± 0.10||0.32 ± 0.10|
|0.06||0.090 ± 0.003||7.8|
|Indinavir||2||0.034 ± 0.001||20||15||0.73 ± 0.10||0.61 ± 0.08|
|6||0.067 ± 0.001||10|
|Itraconazole||15||0.30 ± 0.10||0.61 ± 0.08|
Spectral changes associated with binding of inhibitors to P450 3A4
Effect of cytochrome b5
Kinetics of binding of inhibitors to P450 3A4
SVD analysis of binding
Modeling of inhibition data
- Yamazaki H.
- Johnson W.W.
- Ueng Y.-F.
- Shimada T.
- Guengerich F.P.
Synthesis of 7-OBz quinoline
7-OBz quinoline inhibition assays
7-OBz quinoline rescue assays
Testosterone 6β-hydroxylation inhibition assays
Conflict of interest
Funding and additional information
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