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. Dextromethorphan                     Cmax (ng/ml)   0.685   0.455 ± 0.126   0.610 ± 0.134   0.00 ± 0.00   0.389 ± 0.300 Tmax (h)   0.250   0.250 ± 0.00   0.833 ± 0.144   N.C.   1.50 ± 0.87 t1/2(h) 0.722 N.C. 1.68 ± 0.02 N.C. 1.78 ± 0.14 2.96 ± 3.05 2.66 ± 1.33 N.C. 3.20 ± 1.64 N.C. AUC0-24h (h･ng/ml) 29.8 0.317 93.6 ± 13.2 2.01 ± 1.40 110 ± 9 1.56 ± 0.62 110 ± 1 0.00 ± 0.00 140 ± 16 0.945 ± 0.869 Vd,ss(ml/kg) 12309   9388 ± 1306   10424 ± 721   14637 ± 3426   11448 ± 6222   CLtot (ml/h/kg) 16954   5706 ± 867   4887 ± 343   4818 ± 32   3620 ± 448   BA (%)   1.06   2.15   1.45 ± 0.70   0.00 ± 0.00   0.676 ± 0.70                       Dextrorphan                     Cmax (ng/ml)   0.720   0.363 ± 0.180   0.00 ± 0.00   0.219 ± 0.019   0.612 ± 0.211 Tmax (h)   0.250   0.250 ± 0.00   N.C.   3.33 ± 1.15   2.00 ± 0.00 t1/2 (h)   5.30   N.C   N.C.   N.C.   4.15 ± 3.06 AUC0-24h (h･ng/ml)   1.18   1.36 ± 0.68   0.00 ± 0.00   1.65 ± 0.65   3.95 ± 0.22 AUC0-24h ratio of dextrorphan /dextromethorphan   3.94   0.713   0.00 ± 0.00   N.C.   7.45 ± 5.58

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 4: 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.