Table 1

Effect of cytochrome P450-selective inhibitors on saquinavir oxidation in human small-intestinal microsomes

InhibitorInhibitor Concentration (μM)CYP450Saquinavir Oxidation
% Uninhibited Reaction
M-2M-7
7,8-Benzoflavone11A2/3A465.5176.5
1020.195.8
10013.056.2
Furafylline1-a 0.51A267.870.5
595.6104.3
Fluvoxamine11A2100.599.0
10105.6104.5
Quercetin102C8/3A484.897.0
10045.675.8
Sulfaphenazole102C98695.1
10095.186.9
Mephenytoin102C19100.498.5
10092.295.4
Quinidine12D699.198.5
1083.482.6
Chlorzoxazone12E195.295.4
1096.593.9
Ketoconazole13A4<58.3
3<5<5
Troleandomycin1-a 13A491.392.4
1033.734.7
5017.613.7
Midazolam1-b 503A43.712.3
Cyclosporin1-b 503A428.616.7
  • 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.