| Compounds |
Human |
Mouse |
Rat |
Dog |
Monkey |
Microminipig |
| Caffeine |
|
|
|
|
|
|
| CLint (ml/min/mg protein) |
0.00788 ± 0.00012 |
0.00627± 0.00074 |
0.00312 ± 0.00034 |
0.00359 ± 0.00065 |
0.00398 ± 0.00012 |
0.00667 ± 0.00055 |
| CLint (ml/min/kg)a |
9.11± 0.14 |
24.7± 2.9 |
5.61± 0.61 |
5.16 ± 0.93 |
5.37 ± 0.16 |
5.19 ± 0.43 |
| CLh (predicted, ml/h/kg)b |
|
|
|
|
|
|
| Well Stirred Model |
317 |
952 |
243 |
214 |
229 |
213 |
| Parallel-tube Model |
361 |
1040 |
252 |
227 |
240 |
227 |
| Dispersion Model |
347 |
1013 |
250 |
223 |
237 |
223 |
| Fh (predicted)b |
|
|
|
|
|
|
| Well Stirred Model |
0.744 |
0.824 |
0.927 |
0.885 |
0.912 |
0.877 |
| Parallel-tube Model |
0.709 |
0.807 |
0.924 |
0.878 |
0.908 |
0.869 |
| Dispersion Model |
0.720 |
0.812 |
0.925 |
0.880 |
0.910 |
0.872 |
| Losartan |
|
|
|
|
|
|
| CLint (ml/min/mg protein) |
0.0379± 0.0062 |
0.0876± 0.0080 |
0.0149 ± 0.0020 |
0.0146 ± 0.0027 |
0.122 ± 0.007 |
0.0277 ± 0.0030 |
| CLint(ml/min/kg)a |
43.8± 7.2 |
345± 32 |
26.8 ± 3.5 |
21.1 ± 3.8 |
165 ± 9 |
21.6 ± 2.3 |
| CLh (predicted, ml/h/kg)b |
|
|
|
|
|
|
| Well Stirred Model |
88.8 |
660 |
57.4 |
44.8 |
316 |
45.8 |
| Parallel-tube Model |
92.0 |
702 |
57.9 |
45.4 |
336 |
46.4 |
| Dispersion Model |
91.1 |
690 |
57.8 |
45.2 |
330 |
46.3 |
| Fh (predicted)b |
|
|
|
|
|
|
| Well Stirred Model |
0.929 |
0.878 |
0.983 |
0.976 |
0.879 |
0.974 |
| Parallel-tube Model |
0.926 |
0.870 |
0.983 |
0.976 |
0.872 |
0.973 |
| Dispersion Model |
0.927 |
0.872 |
0.983 |
0.976 |
0.874 |
0.973 |
| Omeprazole |
|
|
|
|
|
|
| CLint (ml/min/mg protein) |
0.0354± 0.0042 |
0.0590± 0.0050 |
0.136 ± 0.008 |
0.0112 ± 0.0012 |
0.117 ± 0.006 |
0.0260 ± 0.0070 |
| CLint (ml/min/kg)a |
41.0± 4.9 |
232± 20 |
245 ± 15 |
16.2± 1.7 |
158 ± 8 |
20.2 ± 5.5 |
| CLh (predicted, ml/h/kg)b |
|
|
|
|
|
|
| Well Stirred Model |
147 |
804 |
765 |
63.6 |
516 |
78.6 |
| Parallel-tube Model |
156 |
866 |
860 |
64.7 |
570 |
80.4 |
| Dispersion Model |
153 |
848 |
831 |
64.4 |
553 |
79.9 |
| Fh (predicted)b |
|
|
|
|
|
|
| Well Stirred Model |
0.882 |
0.851 |
0.769 |
0.966 |
0.803 |
0.955 |
| Parallel-tube Model |
0.874 |
0.840 |
0.740 |
0.965 |
0.782 |
0.954 |
| Dispersion Model |
0.877 |
0.843 |
0.749 |
0.965 |
0.788 |
0.954 |
| Dextromethorphan |
|
|
|
|
|
|
| CLint (ml/min/mg protein) |
0.0327± 0.0066 |
0.167± 0.007 |
0.489 ± 0.001 |
0.0585± 0.007 |
0.669 ± 0.008 |
0.582 ± 0.011 |
| CLint (ml/min/kg)a |
37.8± 7.6 |
658± 27 |
880 ± 1 |
84.3 ± 9.8 |
903 ± 11 |
453 ± 8 |
| CLh (predicted, ml/h/kg)b |
|
|
|
|
|
|
| Well Stirred Model |
532 |
4049 |
2872 |
978 |
2340 |
1500 |
| Parallel-tube Model |
655 |
5130 |
3307 |
1247 |
2615 |
1731 |
| Dispersion Model |
615 |
4837 |
3257 |
1158 |
2597 |
1704 |
| Fh (predicted)b |
|
|
|
|
|
|
| Well Stirred Model |
0.572 |
0.250 |
0.133 |
0.472 |
0.105 |
0.135 |
| Parallel-tube Model |
0.473 |
0.050 |
0.001 |
0.327 |
0.000206 |
0.00162 |
| Dispersion Model |
0.505 |
0.104 |
0.017 |
0.375 |
0.00721 |
0.0175 |
| Midazolam |
|
|
|
|
|
|
| CLint (ml/min/mg protein) |
0.569± 0.018 |
0.460± 0.016 |
0.472 ± 0.028 |
0.528 ± 0.020 |
0.973 ± 0.058 |
0.246 ± 0.043 |
| CLint (ml/min/kg)a |
658± 21 |
1811± 62 |
850 ± 50 |
736 ± 70 |
1314 ± 78 |
192 ± 34 |
| CLh (predicted, ml/h/kg)b |
|
|
|
|
|
|
| Well Stirred Model |
787 |
2826 |
1512 |
1047 |
1626 |
461 |
| Parallel-tube Model |
1022 |
3598 |
1883 |
1348 |
2110 |
527 |
| Dispersion Model |
947 |
3343 |
1761 |
1249 |
1954 |
506 |
| Fh (predicted)b |
|
|
|
|
|
|
| Well Stirred Model |
0.366 |
0.477 |
0.543 |
0.435 |
0.378 |
0.734 |
| sParallel-tube Model |
0.177 |
0.334 |
0.432 |
0.273 |
0.193 |
0.696 |
| Dispersion Model |
0.238 |
0.381 |
0.468 |
0.326 |
0.253 |
0.708 |
|
Each in vitro intrinsic clearance value represents mean ± SD for triplicate determinations.
aCalculated using standard values of 45 mg of microsomal protein/g liver [3] for all species and the following values for g liver/kg body weight: human, 25.7; mouse, 87.5;
rat, 40.0; dog, 32.0; monkey, 32.0 [4]; microminipig, 17.3.
bCalculated as described previously [3]. Blood flow rates in human, mouse, rat, dog, monkey, and microminipig livers were 20.7, 90.0, 55.2, 30.9, 43.6, and 28.9 ml/min/kg, respectively [4,5]. Prasma protein binding and blood-to-plasma ratios for each drug were used human values for all species [6-8].
CLint, in vitro intrinsic clearance value; CLh, hepatic clearance; Fh, hepatic availability. |
