TABLE 9

Summary of predictions of drug-drug interactions for CYP3A


Inhibiting Drug

IC50 (μM)a

fu

Affected Drug

Largest Predicted Magnitude of Drug Interactionb

Actual Drug Interaction
Testosterone
Midazolam
Felodipine
[I] = Csys
[I] = fu × Csys
[I] = Chep,inlet(est)
[I] = fu × Chep,inlet(est)
Alprazolam >300 >300 >300 0.29 Buspirone 1.00 1.00 1.00 1.00 1.29
Atenolol >300 >300 >300 1 Nifedipine 1.02 1.02 1.03 1.03 0.98
Atorvastatin 300 16 36 0.02 Midazolam i.v. 1.00 1.00 1.07 1.00 1.41
Azithromycin >300 >300 >300 0.12 Midazolam 1.05 1.05 1.07 1.05 1.27
Buspirone 70 59 >300 0.05 Alprazolam 1.00 1.00 1.04 1.00 1.08
Caffeine >300 >300 >300 0.64 Alprazolam 1.02 1.01 1.03 1.02 1.08
Cimetidinec 230 >300 >300 0.79 Triazolam 1.29 1.27 1.75 1.64 2.20
Citalopram >300 >300 >300 0.20 Alprazolam 1.00 1.00 1.00 1.00 1.02
Clarithromycinc >300 99 >300 0.30 Midazolam 1.42 1.36 2.00 1.54 9.61
Cyclosporin 4.5 1.4 300 0.07 Simvastatin 2.52 1.54 4.83 1.74 2.55
Digoxin >300 >300 >300 0.75 Nifedipine 1.00 1.00 1.00 1.00 0.98
Diltiazemc 60 83 >300 0.22 Buspirone 1.40 1.39 1.76 1.48 5.33
Disulfiram 6.9 3.6 7.9 0.04 Midazolam 1.74 1.74 13.8 2.70 0.94
Erythromycinc 220 18 16 0.16 Buspirone 4.64 3.42 12.2 4.95 5.91
Fluconazole 17 6.8 23 0.89 Midazolam 7.64 7.15 10.5 9.86 3.60
Fluoxetine 16 36 88 0.05 Alprazolam 1.04 1.01 1.16 1.01 1.32
Fluvoxamine 28 43 62 0.23 Buspirone 2.41 2.38 3.40 2.61 2.40
Gatifloxacin >300 >300 >300 0.80 Midazolam i.v. 1.02 1.01 1.06 1.05 1.08
Gemfibrozil >300 >300 >300 0.03 Simvastatin 1.31 1.15 1.51 1.15 1.43
Itraconazole 0.010 0.045 0.021 0.002 Buspirone 59.5 5.56 67.3 14.3 18.2
Ketoconazole 0.012 0.011 0.019 0.01 Midazolam 24.5 8.50 25.0 18.2 17.0
Metoprolol >300 >300 >300 0.89 Nifedipine 1.02 1.02 1.05 1.05 1.05
Metronidazole >300 >300 >300 0.89 Midazolam 1.39 1.36 1.59 1.55 0.93
Mibefradilc 0.33 0.19 0.68 0.005 Midazolam 10.3 1.82 20.0 2.16 8.86
Nefazodonec 1.4 0.90 8.6 0.009 Midazolam 10.3 1.87 19.6 2.42 5.44
Nelfinavirc 0.65 0.17 0.18 0.015 Simvastatin 19.3 3.54 21.4 12.7 6.07
Omeprazole 110 68.4 >300 0.05 Nifedipine 1.05 1.04 1.08 1.04 1.25
Paroxetine 23 23 17 0.05 Alprazolam 1.02 1.01 1.12 1.01 0.99
Propoxyphene 72 84 140 0.24 Alprazolam 1.01 1.01 1.31 1.08 1.60
Propranolol 140 >300 >300 0.10 Alprazolam 1.01 1.00 1.26 1.03 1.38
Quinidine 140 58 >300 0.13 Nifedipine 1.31 1.24 2.69 1.44 1.37
Ranitidine >300 >300 >300 0.85 Midazolam 1.05 1.05 1.09 1.08 1.69
Repaglinide 180 >300 120 0.026 Nifedipine 1.00 1.00 1.01 1.00 1.09
Ritonavirc 0.0088 0.0042 0.0037 0.015 Triazolam 22.2 17.0 22.3 20.3 20.3
Roxithromycin >300 68 >300 0.14 Midazolam 1.53 1.24 1.74 1.27 1.47
Saquinavirc 2.0 0.82 0.51 0.02 Midazolam 16.9 2.58 24.4 10.9 5.17
Sertraline 8.6 16 18 0.02 Alprazolam 1.05 1.01 1.52 1.02 1.00
Simvastatin 2.0 0.77 2.6 0.06 Midazolam 1.65 1.49 2.32 1.53 1.13
Terbinafine >300 >300 >300 0.01 Midazolam 1.07 1.06 1.10 1.06 0.75
Troleandomycinc 9.3 2.6 12 0.15 Midazolam 3.72 2.05 14.8 5.54 4.10
Venlafaxine >300 >300 >300 0.73 Alprazolam 1.00 1.00 1.02 1.01 0.98
Verapamilc
23
23
50
0.10
Midazolam
1.45
1.40
2.62
1.52
2.91
  • a Used a value of IC50 = 1000 μM for those drugs for which the measured value was greater than 300 μM

  • b Prediction is made from the most potent in vitro IC50 of the three activities

  • c Denotes mechanism-based inactivators of CYP3A