TABLE 6

Potential in vivo significance of differential inhibition of probe substrate metabolism in CYP2C9.1 and CYP2C9.3 variants

Inhibitors
Estimated In Vivo Cmaxa
Ratio of Predicted in Vivo % Activity Remaining for CYP2C9.1/Predicted in Vivo % Activity Remaining for CYP2C9.3b
Flurbiprofen
Warfarin
Phenytoin
Tolbutamide
Diclofenac
μM
Mibefradil 1.0 1.0* 0.8 1.0* 1.0* 1.0*
Indomethacin 15.4 1.1* 0.2 1.2 1.1 1.0*
Benzbromarone 2.9 0.0 0.1 0.1 0.7 0.4
Sulfaphenazole 169 0.1 0.8 0.8 0.9 0.7
Nicardipine 0.49 0.4 1.2 12.4 2.2 1.9
(S)-Ibuprofen 172 0.5 1.0 1.0 0.4 0.5
Amiodarone 5.4 1.0* 5.4 2.0 1.1 1.4
Sulfamethizole 74.0 0.7 0.6 0.8 0.5 0.8
Omeprazole 3.0 0.9* 0.8 1.4 0.9 1.8
Clozapine 1.4 0.9* 1.1* 1.1* 1.1* 1.0*
Gemfibrozil 118 1.0 0.5 0.7 0.6 0.5
Ketoconazole 7.0 0.4 1.1 2.8 2.7 2.2
Progesterone 0.02 1.0* 1.0* 1.0* 1.0* 1.0*
Nifedipine 0.39 1.0* 1.1 1.3 1.6 1.0*
Thiobendazole N.A. N.A. N.A. N.A. N.A. N.A.
Quinine 13.3 0.2 1.0 1.1* 1.0* 1.0*
Quercetin 4.5 4.2 2.3 1.3 2.2 1.5
Fluvoxamine 0.15 0.9* 1.0* 1.0* 1.0* 1.0*
Tamoxifen 0.54 1.0* 1.1 1.0* 1.1* 1.0*
Miconazole 14.9 0.3 0.7 1.4 1.2 0.8
α-Naphthoflavone N.A. N.A. N.A. N.A. N.A. N.A.
Diclofenac 6.3 0.6 1.1 0.8 0.5
Flurbiprofen 17.2 0.7 1.0 0.9 0.9
Warfarin 1.8 1.2* 0.9* 0.8 0.9*
Phenytoin 14.4 0.6 0.8 1.2 1.0
Tolbutamide 189 0.2 0.4 1.2 0.6
Piroxicam 7.5 0.1 0.8 1.3 1.4 1.0
Vivid Green N.A. N.A. N.A. N.A. N.A. N.A.
Dapsone
10.0
Activator
0.4
1.0
1.0
0.8

  • N.A., not applicable. Literature values for Cmax were not identified.

  • ↵ a Values are the estimated Cmax for each inhibitor and were obtained from the literature. Individuals who are homozygous or heterozygous for CYP2C9*3 would like exhibit higher Cmax values.

  • ↵ b Values less than 1.0 indicate greater inhibition of CYP2C9.1-mediated metabolism of the probe substrate. Values greater than 1.0 indicate greater inhibition of CYP2C9.3-mediated metabolism of the probe substrate. In both cases, the farther the deviation is from 1.0, the greater the difference in inhibition of the two isoforms. The ratio values represent the worst case scenario, individuals homozygous for CYP2C9*3.

  • ↵* Values marked with an asterisk indicate that the percentage inhibition predicted would be less than 30% for both isoforms and, thus, not likely to be clinically relevant.