Table 3.
Multispecies intrinsic clearance (CLint) estimated from S9 fractions containing NADPH, containing NADPH and hydralazine, without NADPH, or containing hydralazine without NADPH, and the estimated fraction metabolized by AO (Fm,AO) calculated from the CLint data using methods A and B.
| Species | CLint (mL/min/kg) | Fm,AO | ||||
|---|---|---|---|---|---|---|
| +NADPH | +NADPH +Hyd | −NADPH | −NADPH +Hyd | Method A | Method B | |
| Zaleplon | ||||||
| Human | 5.57 ± 1.01 | n/c | 3.96 ± 1.35 | n/c | 1 | 0.71 |
| Mouse | 28.0 ± 2.81 | 22.0 ± 6.14 | n/c | n/c | 0.22 | 0 |
| Rat | 18.0 ± 0.698 | n/c | n/c | n/c | n/a | n/a |
| Guinea Pig | 13.5 ± 1.90 | n/c | 6.73 ± 3.63 | n/c | 1 | 0.50 |
| Cynomolgus Monkey | 18.3 ± 1.41 | n/c | 12.8 ± 1.34 | n/c | 1 | 0.70 |
| Rhesus Monkey | 16.7 ± 1.31 | 9.61 ± 0.964 | 10.8 ± 0.743 | n/c | 0.42 | 0.65 |
| Minipig | 6.70 ±0.621 | 5.54* | n/c | n/c | 0.17 | 0 |
| O6-benzylguanine | ||||||
| Human | 17.8 ± 3.05 | 5.37 ± 1.16 | 14.8 ± 1.98 | n/c | 0.70 | 0.83 |
| Mouse | 15.5 ± 2.48 | n/c | n/c | n/c | n/a | n/a |
| Rat | 6.59 ± 0.664 | n/c | n/c | n/c | n/a | n/a |
| Guinea Pig | 58.7 ± 4.65 | 15.0 ± 2.14 | 48.7 ± 5.15 | n/c | 0.74 | 0.83 |
| Cynomolgus Monkey | 35.6 ± 5.10 | n/c | 33.5 ± 3.84 | n/c | 1 | 0.94 |
| Rhesus Monkey | 19.5 ± 2.05 | n/c | 21.3 ± 1.52 | n/c | 1 | 1# |
| Minipig | 4.68 ± 2.20 | n/c | n/c | n/c | n/a | n/a |
| Zoniporide | ||||||
| Human | 17.0 ± 1.49 | 4.00 ± 0.442 | 17.1 ± 1.53 | 4.80 ±0.685 | 0.77 | 0.72 |
| Mouse | 331 ± 17.5 | 31.7 ± 1.12 | 297 ± 16.0 | n/c | 0.90 | 0.90 |
| Rat | 482 ± 13.9 | 125 ± 11.0 | 357 ± 25.1 | 9.70 ± 1.90 | 0.74 | 0.72 |
| Guinea Pig | 73.6 ± 2.61 | 11.6 ± 2.06 | 84.4 ± 2.75 | 12.9 ± 2.54 | 0.84 | 0.97 |
| Cynomolgus Monkey | 55.2 ± 1.73 | 5.74 ± 1.16 | 55.3 ± 1.63 | n/c | 0.90 | 1 |
| Rhesus Monkey | 27.8 ± 2.03 | 6.47 ± 3.97 | 31.2 ± 2.60 | n/c | 0.77 | 1# |
| Minipig | 22.1 ± 1.87 | 3.67 ± 1.55 | 21.5 ± 1.01 | n/c | 0.83 | 0.97 |
| BIBX1382 | ||||||
| Human | 71.6 ± 1.92 | 5.83 ± 1.22 | 69.6 ± 2.10 | 3.93 ± 1.75 | 0.92 | 0.92 |
| Mouse | 21.4 ± 10.9 | n/c | n/c | n/c | n/a | n/a |
| Rat | 27.6 ± 0.995 | 25.1 ± 6.29 | 19.0 ± 3.17 | n/c | 0.09 | 0.69 |
| Guinea Pig | 69.4 ± 1.66 | 24.5 ± 2.92 | 50.4 ± 1.13 | n/c | 0.65 | 0.73 |
| Cynomolgus Monkey | 172 ±1.26 | n/c | 209 ± 19.6 | n/c | 1 | 1# |
| Rhesus Monkey | 108 ± 5.43 | 6.03 ± 3.34 | 92.7 ± 1.21 | n/c | 0.94 | 0.86 |
| Minipig | 133 ± 6.98 | 20.0 ± 2.92 | 127 ± 7.08 | n/c | 0.85 | 0.96 |
| SGX523 | ||||||
| Human | 7.34 ± 3.34 | 4.70 ± 2.40 | 4.51 ± 0.310 | n/c | 0.36 | 0.61 |
| Mouse | 35.9 ± 10.3 | 24.2 ± 5.04 | 24.4 ± 9.31 | 16.5 ± 4.03 | 0.33 | 0.22 |
| Rat | 36.9 ± 4.23 | 21.4 ± 0.664 | 10.4 ± 3.20 | n/c | 0.42 | 0.28 |
| Guinea Pig | 38.2 ± 1.13 | 29.4 ± 3.05 | 15.8 ± 6.15 | 14.6 ± 6.05 | 0.23 | 0.03 |
| Cynomolgus Monkey | 39.4 ± 1.25 | 16.6 ± 3.42 | 26.9 ± 4.35 | n/c | 0.58 | 0.68 |
| Rhesus Monkey | 23.6 ± 4.13 | 15.6 ± 2.43 | 11.3 ± 0.942 | 7.97 ± 3.59 | 0.34 | 0.14 |
| Minipig | 26.0 ± 1.20 | 21.4 ± 1.98 | 3.20 ± 0.574 | n/c | 0.18 | 0.12 |
CLint data represent means of triplicate determinations (±SD); Fm,AO calculated using mean CLint values
n/c = CLint not calculated; mean ln[C] versus time slope not significantly different from zero
n/a = insufficient CLint data to calculate Fm,AO
*
mean of duplicate determinations
#
calculations resulting in an Fm,AO > 1 were assumed to be equal to 1