TABLE 2

Enzyme kinetic parameters for formation of clozapine metabolites by HLM and recombinant human CYP3A4 and CYP2D6

Metabolite	Kinetic Parameters	Enzyme Fractions
Metabolite	Kinetic Parameters	CYP3A4	CYP2D6	Pooled HLM
Total GSH conjugates	K_M (µM)	30.3 ± 5.1	21.9 ± 2.7	126 ± 22
	V_max (nmol/min/nmol P450)	3.1 ± 0.1	2.8 ± 0.1	1266 ± 89^a
	V_max/K_M (ml/min/nmol P450; ×10³)	101.9	128.8	10071^b
Clozapine N-Oxide	K_M (µM)	92.7 ± 5.5	84.1 ± 3.9	250 ± 39
	V_max (nmol/min/nmol P450)	9.5 ± 0.2	6.1 ± 0.1	2130 ± 164^a
	V_max/K_M (ml/min/nmol P450; ×10³)	102.5	72.8	8516^b
N-Demethyl Clozapine	K_M (µM)	47.6 ± 4.4	25.3 ± 0.4	268 ± 37
	V_max (nmol/min/nmol P450)	19.9 ± 0.6	32.8 ± 0.2	3215 ± 226^a
	V_max/K_M (ml/min/nmol P450; ×10³)	419	1298	11974^b

GSH, glutathione; HLM, human liver microsomes.
↵a V_max values for HLM are expressed as nmol/min/mg protein.
↵b V_max/K_M values for HLM are expressed in ml/min/mg protein.