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. Losartan                     Cmax (ng/ml)   1.66   83.4 ± 20.6   73.9 ± 21.5   16.5 ± 1.2   28.7 ± 8.4 Tmax (h)   0.250   1.08 ± 0.88   0.750 ± 0.250   2.67 ± 1.15   1.25 ± 0.66 t1/2(h) 0.0860 1.24 1.87 ± 0.07 2.70 ± 1.12 13.1 ± 7.7 8.07 ± 3.40 4.13 ± 1.33 4.52 ± 1.34 1.82 ± 0.87 3.59 ± 3.02 AUC0-24h (h･ng/ml) 90.9 1.75 1044 ± 69 517 ± 101 464 ± 127 182 ± 76 798 ± 286 107 ± 42 458 ± 160 131 ± 64 Vd,ss(ml/kg) 653   1506 ± 273   8584 ± 5560   1196 ± 585   1222 ± 384   CLtot (ml/h/kg) 9206   849 ± 62   1771 ± 528   1146 ± 432   2015 ± 747   BA (%)   1.92   49.5   38.4 ± 10.2   13.0 ± 3.8   28.7 ± 11.9 EXP3174                     Cmax (ng/ml)   62.3   57.6 ± 14.9   4.33 ± 2.92   8.73 ± 3.85   18.6 ± 15.1 Tmax (h)   0.750   5.33 ± 2.31   1.25 ± 0.66   2.67 ± 1.15   4.00 ± 0.00 t1/2 (h)   2.21   6.11 ± 0.65   11.2 ± 7.7   2.19 ± 0.19   8.01 ± 3.75 AUC0-24h (h･ng/ml)   158   700 ± 89   22.3 ± 18.4   46.1 ± 20.6   173 ± 155 AUC0-24h ratio of EXP3174/losartan   87.3   1.31   0.133 ± 0.092   0.489 ± 0.288   1.57 ± 1.57

Each data represents the mean ± S.D. of three determinations, except for data in mice and, BA and AUC0-24h of EXP3174/losartan in rats. Data in mice are calculated from the average plasma concentration of the three animals. BA and AUC0-24h of EXP3174/losartan 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 2: Pharmacokinetic parameters of losartan and EXP3174 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.