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- Automated Definition of the Enzymology of Drug Oxidation by the Major Human Drug Metabolizing Cytochrome P450s



TABLE 1 CYP isoform characterization of individual HLM pools

Isoform	Probe	Batch 1	Batch 2	Batch 3

		pmol/min/mg
P450 content	CO difference spectrum	320^a	280^a	430^a
P450 reductase	Cytochrome c reduction	69000	84000	75000
CYP	7-Ethoxycoumarin O-demethylation	255	210	240
CYP1A2	Phenacetin O-dethylation	366	310	193
CYP2A6	Coumarin 7-hydroxylation	17200	81900	58600
CYP2E1	Chlorzoxazone 6-hydroxyline	1010	1911	1441
CYP2C	Mephenytoin 4-hydroxylation	27	233	11
CYP2D6	Dextromethorphan O-demethylation	200	84	106
CYP3A	Testosterone 6 $beta$ -hydroxylation	2600	1500	1900
CYP4A	Lauric acid 11-hydroxylation	1000	1600	1600

^a Picomoles of CYP per milligram of microsomal protein.



TABLE 2 Estimated levels of the five major isoforms in HLM pools Mean total level = 320 pmol of CYP · mg¹ of microsomal protein.

Isoform	Mean	References

	%
CYP1A2	13	Shimada et al. (1994), Guengerich and Turvy (1991), Belloc et al. (1996)
CYP2C9	20	Shimada et al. (1994), Becquemont et al. (1998), Wester et al. (2000), Inoue et al. (1997), Lasker et al. (1998)
CYP2C19	4	Wester et al. (2000), Inoue et al. (1997), Lasker et al. (1998)
CYP2D6	2	Shimada et al. (1994), Becquemont et al. (1998), Imaoka et al. (1996)
CYP3A4	30	Shimada et al. (1994), Belloc et al. (1996), Becquemont et al. (1998)



TABLE 3 CL_int of marker substrates in different HLM pools and literature values

Compound	CL_int					References
Compound	Batch 1	Batch 2	Batch 3	Mean	Literature	References

	µl · min¹mg¹
Tolbutamide				0.7^a	0.5-2.5; 1 ± 0.2	Iwatsubo et al. (1997), Doecke et al. (1991), Back et al. (1988), Bourrie et al. (1996), Obach (1999)
Diazepam	3 ± 1	2	2	3 ± 1	2.6 ± 0.8	Obach (1999)
Metoprolol	7 ± 1	5	5	6 ± 1	14, 19	Mautz et al. (1995)
Ibuprofen	14	5	5	8 ± 2	9.6 ± 1.1	Obach (1999)
Propranolol	16 ± 3	16	15	15 ± 0	11-60	Lave et al. (1997), Obach (1997), Otton et al. (1990)
Dextromethorphan	29 ± 3	30	33	29 ± 3	25-103	Kerry et al. (1994), Broly et al. (1990)
Omeprazole	43 ± 7	11	15	34 ± 14	18, 26	Andersson et al. (1993), Kobayashi et al. (1994)
Diltiazem	56 ± 7	22	22	45 ± 16	17 ± 2	Obach (1999)
Testosterone	81 ± 12	23	35	60 ± 18
Verapamil	380 ± 44	111	114	256 ± 100	139 ± 3	Obach (1999)

^a Determined from V_max/K_m. Where determined, results are presented as mean ± S.D.



TABLE 4 Determination of CYP Cl_int of individual human CYPs to oxidative metabolism for marker substrates

Compound	CL_int
Compound	CYP1A2	CYP2C9	CYP2C19	CYP2D6	CYP3A4

	µl · min¹pmol¹
Tolbutamide	N.D.^a	0.014^b	0.03 ± 0.01	N.D.	N.D.
Diazepam	N.D.	N.D.	0.17 ± 0.05	N.D.	N.D.
Metoprolol	N.D.	N.D.	N.D.	1.03 ± 0.07	N.D.
Ibuprofen	N.D.	0.29 ± 0.09	0.17 ± 0.01	N.D.	N.D.
Propranolol	0.34 ± 0.03	N.D.	0.66 ± 0.06	5.07 ± 2.80	N.D.
Dextromethorphan	N.D.	N.D.	0.16 ± 0.10	1.97 ± 0.24	N.D.
Omeprazole	N.D.	N.D.	6.95 ± 1.93	N.D.	0.44 ± 0.06
Diltiazem	N.D.	N.D.	0.30 ± 0.04	N.D.	0.58 ± 0.04
Testosterone	N.D.	N.D.	N.D.	N.D.	0.42 ± 0.03
Verapamil	N.D.	N.D.	N.D.	N.D.	1.19 ± 0.12

^a N.D., not detectable (<0.02 µl · min¹ · pmol¹).
^b Determined from V_max/K_m. Mean ± S.D. for n = 3 separate experiments.



TABLE 5 Mean percentage contribution of individual CYPs to oxidative metabolism

Compound	CYP1A2	CYP2C9	CYP2C19	CYP2D6	CYP3A4	Literature

	%
Tolbutamide		70	30			2C
Diazepam			100			2C19>3A
Metoprolol				100		2D6
Ibuprofen		90	10			2C9
Propranolol	26		15	59		2D6, 1A2, 2C19
Dextromethorphan			14	86		2D6>3A
Omeprazole			68		32	2C19 $z.Gt.gif$ 3A
Diltiazem			7		93	3A
Testosterone					100	3A
Verapamil					100	3A



TABLE 6 Determination of CYP Cl_int for marker and AR-C compounds

Compound	CL_int
Compound	HLM	CYP

	µl · min¹mg¹
Tolbutamide	0.7^a	1.3^a
Diazepam	3 ± 1	2 ± 1
Metoprolol	6 ± 1	7 ± 0
Ibuprofen	8 ± 2	20 ± 5
Propranolol	15 ± 0	55 ± 15
Dextromethorphan	29 ± 3	14 ± 1
Omeprazole	34 ± 14	131 ± 25
Diltiazem	45 ± 16	60 ± 3
Testosterone	60 ± 18	40 ± 3
Verapamil	256 ± 100	114 ± 11

^a Determined from V_max/K_m. Mean ± S.D.

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