Pharmacokinetic
Parameters
Mouse Rat Dog Monkey Microminipig
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

                   
Cmax (ng/ml)   11.1   0.493 ± 0.407   4.75 ± 1.35   0.469 ± 0.226   0.383 ± 0.071
Tmax (h)   0.250   0.250 ± 0.00   0.417 ± 0.144   2.00 ± 0.00   0.917 ± 0.144
t1/2 (h)   2.31   N.C.   0.577 ± 0.404   N.C.   20.7 ± 27.2
AUC0-24h (h・ng/ml)   9.52   0.320 ± 0.442   5.56 ± 1.05   1.12 ± 0.77   0.917 ± 0.212
AUC0-24h 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 AUC0-24h of dextrorphan/dextromethorphan in rats are calculated using the average AUC0-24h of the three animals.
i.v., intravenous; p.o., peroral; Cmax, the peak plasma concentration; Tmax, the time to reach Cmax; t1/2, terminal elimination half-life; AUC0-24h, area under the plasma concentration
vs. time curve from 0 h to 24 h; Vd,ss, volume of distribution; CLtot, 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.