TABLE 4

Testing RMet using compounds with clinical drug-drug interaction data

ParentMetaboliteRequires Further Analysis for DDIa
Clinical DDIbCytochrome P450IKiI/KiIKiI/KiParent Ki/4RMetParent I/KiMetabolite I/KiRMetOverallc
µMµMµMµMµM
Pd
 Fluoxetine7.82D60.370.21.850.380.21.90.057.6YYYY
 Itraconazole36.43A40.948.50.111.09260.042.130.51YNYY
 Sulfinpyrazone1.92C9512290.2236271.3357.30.63YYYY
 Omeprazole1.52C191.620.80.388.20.050.50.76YNYY
 Quinidine M142.62D61.90.36.330.32.30.130.0754YYYY
 Quinidine M242.62D61.90.36.330.643.50.010.0758YNYY
Md
 Amiodarone2.12C91.09390.031.165.90.29.80.12NYYY
 Bupropion M15.22D60.67210.032.345.40.435.250.36NYYY
 Bupropion M25.22D60.67210.034.01130.35.250.61NYYY
 Bupropion M35.22D60.67210.030.431.70.255.250.08NYNY
 Gemfibrozil82C8100601.6720121.67151.33YYYY
 Sertraline1.43A40.333.50.090.533.50.150.8750.61NYYY
Ud
 Omeprazole1.33A41.62010.010.38188050.30.01NNNN
 Ranolazine1.93A42.2900.020.891040.0122.50.04NNNN
 Sertraline1.72D60.25230.010.32160.025.750.06NNNN
 Venlafaxine1.32D60.23300.010.032007.50NNNN
Pfizer clinical compounds
 PF-011.352D60.51350.0150.98>50<0.018.80.11NNYY
 PF-03<1.23A40.0140.00180.08>85<0.000941.00.08NNNN
 PF-06<1.23A40.149.50.0150.14>30<0.00472.40.059NNNN
 PF-072.22D60.110.091.22.2>30<0.080.02398YNYY
 PF-081.43A40.870.392.241.8>30<1.40.098429YNYY
  • RMet, = metabolite I/(parent Ki × 0.25); P, parent-mediated DDI; M, metabolite-mediated DDI; U, unexplained DDI; N, no; Y, yes.

  • a If parent or metabolite I/Ki or RMet is >0.1, then listed as Y; if <0.1, then listed as N.

  • b Clinical DDI, reported AUCI/AUC of victim drug in clinical DDI study.

  • c If parent or metabolite I/Ki or RMet is Y, then overall is Y.

  • d Data on literature cytochrome P450 inhibitors from The University of Washington Metabolism and Transport Drug Interaction Database