TABLE 3

Metabolic pathway, apparent intrinsic clearance, and f_m(AO) identified for 10 selected compounds and compared in two human hepatocyte batches

Metabolic pathways were confirmed using biotransformation. Human hepatocytes were suspended at 1.5 million cells/ml. Termination time points = 0, 5, 15, 30, 60, 120, and 240 min; n = 3/time point. Cl_{int, app} values were calculated from averaged AUC_0–∞ extrapolated data. Batch 1: pooled lots AGR, FKM, EHI, TDH, and ZFB; batch 2: lot RTH.

Drug	Metabolic Pathways	Cl_{int, app}						f_m(AO)
		Batch 1			Batch 2			f_m(AO)
		No Hydralazine	25 μM Hydralazine	50 μM Hydralazine	No Hydralazine	25 μM Hydralazine	50 μM Hydralazine	Batch 1^{^a}	Batch 2^{^b}
		μl · min⁻¹ · 10⁶ cells⁻¹
O⁶-Benzylguanine	AO	23.8	N.C.	N.C.	21.0	7.50	3.65	N.C.	0.83
PF-0945863	AO, N-demethylation	23.9	N.C.	N.C.	24.8	11.5	9.61	N.C.	0.61
Zaleplon	AO, N-deethylation	11.5	3.47	3.08	10.9	6.95	4.82	0.70	0.56
Zoniporide	AO, hydrolysis	22.0	7.97	5.08	18.3	12.9	8.16	0.64	0.55
DACA	AO, N-demethylation	55.5	25.9	21.2	51.7	22.6	12.6	0.53	0.76
Carbazeran	AO, glucuronidation	73.9	37.8	27.2	67.2	37.1	30.1	0.49	0.55
Propranolol	Hydroxylation, glucuronidation	305	198	179	294	245	236	0.35	0.20
Midazolam	Hydroxylation	34.3	31.7	32.5	43.5	45.9	41.3	0.08	0.05
Naloxone	Hydroxylation, glucuronidation	56.9	52.9	54.5	48.3	57.4	56.9	0.07	N.D.
Dextromethorphan	N-Demethylation^{^c}	—	—	—	30.9	29.0	18.7	—	0.39

N.C., Cl_{int, app} in the presence of hydralazine could not be calculated because the slope of the ln[C] versus time curve was not statistically different from zero, which precluded a reliable measurement; N.D., not determined; —, compound not run in assay.
↵a f_m(AO) was determined using 25 μM hydralazine data.
↵b f_m(AO) was determined using 50 μM hydralazine data.
↵c Data from Gorski et al. (1994).