TABLE 4

Use of cytochrome P4503A4 intersystem extrapolation factors from three substrates in the estimation of fractional metabolism values for omeprazole

	ISEF Parameters			CL_int		f_m
rCYP	Reaction	ISEF Value	CYP Abundance units of pmol/mg microsomal protein	rCYP CL_int,u (µL/min/pmol P450)	ISEF-derived HLM CL_int,sc,u (mL/min/kg)^a	In Vitro f_m	In Vivo f_m
rCYP3A4	1’-Hydroxymidazolam Formation	0.26			75.4	0.60	0.27^b
	Vardenafil Depletion	0.29	137	2.35	84.1	0.63
	Quinidine Depletion	0.044			12.8	0.21

rCYP2C19	(S)-Mephenytoin 4’-Hydroxylation	0.50^c	14	7.84	49.4	0.37-0.79	0.85^d

^aBinding values were scaled using the equation described in Austin et al. (2002), from values generated via equilibrium dialysis. Measured unbound fraction in microsomes for omeprazole was 0.90 at 0.71 mg/ml, which scaled to f_u,mic of 0.98, 0.99, and 0.87 for heterologously expressed individual P4503A4, heterologously expressed individual P4502C19, and human liver microsome incubations, respectively.
^bCalculated from clinical data reported in Bottiger, et al., 1997.
^cCytochrome P450C19 intersystem extrapolation factor determined from mephenytoin 4’-hydroxylase activity (internal data on file, Pfizer, Inc.) This intersystem extrapolation factor has been used successfully for other CYP2C19 cleared drugs.
^dMedian fractional metabolism value calculated from fifty clinical studies in which omeprazole was dosed to cytochrome P450C19 extensive and poor metabolizers, obtained from the University of Washington Drug Interaction Database.