Table 3.

Rank order analysis of the in vitro Cl_i,f and the in vivo AUC_m/AUC_p for M/P pairs of a given parent drug.

Parent	Metabolite	In vitro Cli,f (µL/min/mg)	In vivo AUCm/AUCp	Rank Order Correctly?	References
Alprazolam	1-hydroxyalprazolam	0.51	0.11	No	1, 2, 3
	4-hydroxyalprazolam	4.1	0.034
Atorvastatin	2-hydroxyatorvastatin	20	0.87	Nob	4, 5
	4-hydroxyatorvastatin	9.1	0.88
Caffeine*	Theophylline	0.072	0.14	Yes	6, 7
	Paraxanthine	1.4	0.48
	Theobromine	0.019	0.080
Clomipramine	2-hydroxyclomipramine	0.98	NDa	Nob	8, 9
	8-hydroxyclomipramine	0.94	0.36
	N-desmethylclomipramine	16	2.2
Codeine*	Morphine	0.23	0.029	No	10, 11, 12
	Norcodeine	1.1	0.25
	Codeine-6-glucuronide	0.45	9.2
Imipramine*	Desipramine	8.3	0.54	Yes	13, 14
	2-hydroxyimipramine	2.8	0.37
Lansoprazole	5-hydroxylansoprazole	19	0.085	No	15, 16
	Lansoprazole sulfone	10	0.61
Morphine*	Morphine-3-glucuronide	8.4	23	Yes	17, 18
	Morphine-6-glucuronide	1.8	2.8
Nefazodone	Hydroxynefazodone	239	0.36	Yes	2, 19
	Meta-chlorophenylpiperazine	190	0.090
Omeprazole	5-hydroxyomeprazole	24	0.92	Yes	20, 21
	Omeprazole sulfone	20	0.54
Propafenone	5-hydroxypropafenone	530	0.50	Yes	22, 23
	N-desalkylpropafenone	3.5	0.064
Quinidine	3-hydroxyquinidine	15	0.24	No	24, 25
	Quinidine N-oxide	2.9	0.37
Tamoxifen	4-hydroxytamoxifen	2.3	0.034	Yes	26, 27
	N-desmethyltamoxifen	31	2.1
Theophylline*	3-methylxanthine	0.012	0.035	Nob	28, 29
	1,3-dimethyluric acid	0.16	0.032

Notes: The in vitro Cl_i,f and in vivo AUC_m/AUC_p values are provided. Additionally, whether or not the metabolites of a given parent rank ordered correctly with respect to these two values is provided. All in vivo AUC_m/AUC_p values were determined under steady-state conditions except for those parent drugs marked with an asterisk, which were determined after single dose administration.

Superscript ‘a’ indicates a value not determined because the observed in vivo metabolite concentrations were not detectable.

Superscript ‘b’ indicates a set of M/P pairs for a given parent drug that were considered to not rank order correctly because the in vitro Cl_i,f values exhibited a > 15% difference but the AUC_m/AUC_p values did not or the AUC_m/AUC_p values exhibited a > 15% difference but the in vitro Cl_i,f values did not. Reference numbers coincide with the below provided references and not with the bibliography references.

References: 1Buch et al, 1993; 2Greene et al, 1995; 3Hirota et al, 2001; 4Park et al, 2008; 5Tekturna New Drug Application, 2007; 6Labedzki et al, 2002; 7Akinyinka et al, 2000; 8Kramer-Nielsen et al, 1996; 9Linnoila et al, 1982; 10Soars et al, 2001; 11Yue et al, 1997; 12Yue et al, 1991b; 13Skelbo et al, 1992; 14Koyama et al, 1994; 15Ieira et al, 2001; 16Kim et al, 2003; 17Morrish et al, 2006; 18Eliot et al, 2002; 19VonMoltke et al, 1999; 20Shirai et al, 2001; 21Shu et al, 2000; 22Dilger et al, 1999; 23Hemeryck et al, 2000; 24Nielsen et al, 1999; 25Schellens et al, 1991; 26Desta et al, 2004; 27Lien et al, 1990; 28Tjia et al, 1996 and 29Rodopoulos et al, 1996.