Inhibitor | Inhibitor Concentration (μM) | CYP450 | Saquinavir Oxidation | |
---|---|---|---|---|
% Uninhibited Reaction | ||||
M-2 | M-7 | |||
7,8-Benzoflavone | 1 | 1A2/3A4 | 65.5 | 176.5 |
10 | 20.1 | 95.8 | ||
100 | 13.0 | 56.2 | ||
Furafylline1-a | 0.5 | 1A2 | 67.8 | 70.5 |
5 | 95.6 | 104.3 | ||
Fluvoxamine | 1 | 1A2 | 100.5 | 99.0 |
10 | 105.6 | 104.5 | ||
Quercetin | 10 | 2C8/3A4 | 84.8 | 97.0 |
100 | 45.6 | 75.8 | ||
Sulfaphenazole | 10 | 2C9 | 86 | 95.1 |
100 | 95.1 | 86.9 | ||
Mephenytoin | 10 | 2C19 | 100.4 | 98.5 |
100 | 92.2 | 95.4 | ||
Quinidine | 1 | 2D6 | 99.1 | 98.5 |
10 | 83.4 | 82.6 | ||
Chlorzoxazone | 1 | 2E1 | 95.2 | 95.4 |
10 | 96.5 | 93.9 | ||
Ketoconazole | 1 | 3A4 | <5 | 8.3 |
3 | <5 | <5 | ||
Troleandomycin1-a | 1 | 3A4 | 91.3 | 92.4 |
10 | 33.7 | 34.7 | ||
50 | 17.6 | 13.7 | ||
Midazolam1-b | 50 | 3A4 | 3.7 | 12.3 |
Cyclosporin1-b | 50 | 3A4 | 28.6 | 16.7 |
Human small-intestinal microsomes (HG30) were preincubated with inhibitors for 5 min at 37°C in the presence of a NADPH-generating system, and 10 μl of a 0.1 mM saquinavir solution was then added to 0.99 ml of reaction mixture. Incubations were stopped after 15 min by the addition of 1 ml of acetonitrile, and the test tubes were then placed on ice.
↵1-a Mechanism-based inactivators were preincubated with human small-intestinal microsomes for 15 min before the addition of saquinavir.
↵1-b Human intestinal microsomal 3A4 substrates.