Table 5

Pharmacokinetic Parameters	Mouse		Rat		Dog		Monkey		Microminipig
Pharmacokinetic Parameters	i.v.	p.o.	i.v.	p.o.	i.v.	p.o.	i.v.	p.o.	i.v.	p.o.
Midazolam
Cmax (ng/ml)		0.121		0.277 ± 0.187		1.32 ± 0.10		0.484 ± 0.238		2.32 ± 0.66
Tmax (h)		0.250		0.250 ± 0.00		0.333 ± 0.144		1.67 ± 0.58		1.25 ± 0.66
t1/2(h)	0.275	N.C.	0.327 ± 0.032	N.C.	0.555 ± 0.276	0.960 ± 0.662	0.904 ± 0.340	N.C.	1.12 ± 0.28	1.29 ± 0.34
AUC0-24h (h･ng/ml)	5.24	0.380	13.3 ± 2.4	0.160 ± 0.205	21.7 ± 2.1	1.72 ± 0.16	70.5 ± 10.6	1.24 ± 0.91	24.4 ± 4.9	8.04 ± 0.85
Vd,ss(ml/kg)	1624		1002 ± 135		765 ± 301		458 ± 85		1509 ± 636
CLtot (ml/h/kg)	6379		2581 ± 517		1552 ± 141		483 ± 73		1411 ± 281
BA (%)		7.26		1.21		7.94 ± 0.75		1.66 ± 1.01		34.3 ± 10.3

1’-Hydroxymidazolam
C_max (ng/ml)		11.1		0.493 ± 0.407		4.75 ± 1.35		0.469 ± 0.226		0.383 ± 0.071
T_max (h)		0.250		0.250 ± 0.00		0.417 ± 0.144		2.00 ± 0.00		0.917 ± 0.144
t_1/2 (h)		2.31		N.C.		0.577 ± 0.404		N.C.		20.7 ± 27.2
AUC_0-24h (h･ng/ml)		9.52		0.320 ± 0.442		5.56 ± 1.05		1.12 ± 0.77		0.917 ± 0.212
AUC_0-24h ratio of 1’-hydroxymidazolam /midazolam		23.9		1.90		3.07 ± 0.31		0.879 ± 0.389		0.108 ± 0.016

Data in mice are calculated from the average plasma concentration of the three animals.
BA and AUC_0-24h of dextrorphan/dextromethorphan in rats are calculated using the average AUC_0-24h of the three animals.
i.v., intravenous; p.o., peroral; C_max, the peak plasma concentration; T_max, the time to reach C_max; t_1/2, terminal elimination half-life; AUC_0-24h, area under the plasma concentration
vs. time curve from 0 h to 24 h; V_d,ss, volume of distribution; CL_tot, total body clearance; BA, bioavailability; N.C., not calculated.

Table 5: Pharmacokinetic parameters of dextromethorphan and dextrorphan in mice, rats, dogs, monkeys, and microminipigs after the intravenous and oral administrations of 5 CYP substrates such as caffeine, losartan, omeprazole, dextromethorphan, and midazolam.