TABLE 1

Specific activities of oxidative metabolism of CLZ by recombinant human P450s

Specific activities (nmol/min/nmol P450) were calculated by peak areas at 254 nm, assuming that extinction coefficients of GSH conjugates and cyanide adducts are the same as that of CLZ.

Variable	DMCLZ		CLZ-NO		Total of GSH Conjugates^a		Cyanide Adduct
CLZ conc.	10 µM	100 µM	10 µM	100 µM	10 µM	100 µM	100 µM
CYP1A1	0.64 ± 0.02	0.56 ± 0.03	0.24 ± 0.01	0.20 ± 0.02	0.30 ± 0.008	0.32 ± 0.01	0.024 ± 0.003
CYP1A2	1.12 ± 0.01	8.71 ± 0.1	0.55 ± 0.01	3.70 ± 0.1	0.060 ± 0.003	0.25 ± 0.004	0.20 ± 0.01
CYP1B1	1.16 ± 0.01	0.94 ± 0.05	0.84 ± 0.01	0.64 ± 0.07	0.15 ± 0.01	0.15 ± 0.004	0.010 ± 0.001
CYP2A6	n.d.	n.d	n.d.	n.d.	n.d.	n.d.	0.17 ± 0.01
CYP2B6	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.
CYP2C8	0.92 ± 0.01	0.89 ± 0.01	0.10 ± 0.01	0.075 ± 0.006	n.d.	n.d.	0.058 ± 0.002
CYP2C9	0.33 ± 0.02	0.22 ± 0.01	0.065 ± 0.005	0.057 ± 0.01	n.d.	n.d.	0.010 ± 0.001
CYP2C18	4.08 ± 0.05	5.71 ± 0.02	0.025 ± 0.005	0.065 ± 0.01	n.d.	n.d.	0.41 ± 0.02
CYP2C19	6.62 ± 0.03	5.11 ± 0.02	0.71 ± 0.03	0.58 ± 0.005	n.d.	n.d.	0.030 ± 0.003
CYP2D6	8.43 ± 0.2	23.7 ± 1.1	0.51 ± 0.01	1.62 ± 0.1	0.47 ± 0.01	1.60 ± 0.05	0.64 ± 0.07
CYP2E1	n.d.	n.d.	n.d.	n.d.	n.d.	n.d.	n.d
CYP2J2	0.70 ± 0.07	1.40 ± 0.1	0.05 ± 0.01	0.10 ± 0.01	0.009 ± 0.001	0.03 ± 0.03	0.05 ± 0.01
CYP3A4	2.98 ± 0.01	15.3 ± 0.1	2.37 ± 0.02	5.62 ± 0.01	0.87 ± 0.01	1.92 ± 0.01	0.18 ± 0.01
CYP3A5	0.24 ± 0.04	1.29 ± 0.02	0.32 ± 0.04	0.88 ± 0.03	0.15 ± 0.01	0.30 ± 0.01	0.08 ± 0.01

CLZ, clozapine; CLZ-NO, clozapine N-oxide; DMCLZ, N-desmethylclozapine; GSH, glutathione; n.d., not detectable; P450, cytochrome P450.
↵a Involvement of individual P450s in CLZ bioactivation is expressed as formation of total of GSH conjugates and cyanide adduct after 30 minutes incubations of 10 µM or 100 µM CLZ, 50 nM recombinant human P450s, in the presence of 100 µM GSH and 8 µM hGST (human glutathione S-transferase) P1-1 or 1 mM KCN, respectively. The values represent means of two measurements; standard deviations were less than 10%.