TABLE 6

Accuracy of CLint predictions for n = 37 drugs from human cryopreserved hepatocytes

Where in vitro data is taken from more than one published source, the mean in vitro CLint value is calculated.

Substrate
Major P450
Known Direct Glucuronidation
Hepatocyte Predicted CLint (ml/min/kg)
Observed in Vivo CLint (ml/min/kg)
-Fold Under-predictiona
Prediction Range
Codeine CYP2D6, 3A4 Yes (UGT2B7/2B4) 35b 19 0.6 Within 2-fold of in vivo (n = 11)
Naloxone N.A.c Yes (UGT2B7) 284b,d,e 200 0.7
Theophylline CYP1A2 2.6e 2.1 0.8 (63)
Prednisolone CYP3A4 Yes 30e 27 0.9
Caffeine CYP1A2 2.1d,e 2.0 1.0 (4.7)
Antipyrine Multiple 0.67d,e 0.69 1.0 (4.9)
Methylprednisolone CYP3A4 Yes 33e 45 1.4
Chlorpromazine CYP2D6 188e 267 1.4 (11)
Midazolam CYP3A4 200f 314 1.6 (6.9)
Alprazolam CYP3A4 2.1f 3.7 1.8 (1.8)
Propofol CYP2B6 Yes (UGT1A9) 2773b 5052 1.8
Bufuralol CYP2D6 45g 99 2.2 (7.2) Within 2- to 5-fold of in vivo (n = 7)
Desipramine CYP2D6 Yes 74e 167 2.3 (10.5)
Diazepam CYP3A4, 2C19 6.6f 18 2.7 (4.2)
S-Warfarin CYP2C9 1.9g 6.1 3.3 (9.2)
Quinidine CYP3A4 18g 61 3.4 (8.1)
Nifedipine CYP3A4 146g 597 4.1 (9.5)
Flunitrazepam CYP3A4 4.5f 20 4.4 (3.9)
Oxazepam N.A.c Yes (UGT2B15) 6.9e 34 5.0 Within 5- to 10-fold of in vivo (n = 9)
Diclofenac CYP2C9 Yes (UGT2B7/1A9) 98g 561 5.7 (1.3)
Triazolam CYP3A4 11f 66 6.2 (4.9)
Diltiazem CYP3A4 19e 125 6.7 (1.5)
Ibuprofen CYP2C9 Yes (UGT2B7) 12e 80 6.8 (9.8)
Lidocaine CYP2D6, 3A4 21d 157 7.5 (51)
Naproxen CYP2C9, 1A2 Yes (UGT2B7) 1.4b 11 7.6
Imipramine Multiple Yes 49b,d,e 380 7.8 (21)
Dextromethorphan CYP2D6, 3A4 172g 1482 8.6 (34)
Terfenadine CYP3A4 4136g 43,333 11 (1053) >10-fold of in vivo (n = 10)
Propranolol Multiple Yes 39d,e 454 12 (5)
Gemfibrozil CYP3A4 Yes (UGT1A1) 5.5b 67 12
Tolbutamide CYP2C9 0.38g 4.9 13 (3.1)
Lorazepam N.A.c Yes (UGT2B15) 0.95e 14 15
Timolol CYP2D6 4.4d 77 17
Metoprolol CYP2D6 4.3d 75 18 (4.2)
Mephenytoin CYP2C19 3.6g 64 18 (38)
Ketoprofen N.A.c Yes (UGT2B7) 4.7b 129 28
Furosemide
N.A.c
Yes
0.91b,e
162
178

  • ↵ a Values in parentheses indicate the -fold under-prediction observed in microsomal studies.

  • ↵ b In vitro data taken from Soars et al. (2002).

  • ↵ c N.A., not available; therefore, exclusive metabolism by UGT isoforms is assumed.

  • ↵ d In vitro data taken from Shibata et al. (2002).

  • ↵ e In vitro data taken from Lau et al. (2002).

  • ↵ f In vitro data taken from Hallifax et al. (2005).

  • ↵ g In vitro data obtained in this laboratory.