TABLE 6

Accuracy of CL_int 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 CL_int value is calculated.

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