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.
Table 1: Comparison of in vivo pharmacokinetic data with the values predicted from liver microsomal intrinsic clearance in vitro.