TABLE 4

Physiologically scaled in vivo hepatic clearance processes based on hepatocyte data, and IVIVE ESF

ParameterHumanMonkeyRat
Physiologically scaled CLliver,passa (l/h)1315.100.901
 Prospective diffusion ESFb0.145
 Retrospective diffusion ESFc0.1820.9530.0357
Physiologically scaled kliver,uptaked (nmol/h)1.17 × 1063.53 × 1043.26 × 104
 Prospective uptake ESF10.3
 Retrospective uptake ESF4.0817.73.96
Physiologically scaled kliver,metabolism (nmol/h)2.85 × 1061.15 × 104
 Prospective metabolism ESF0.155
 Retrospective metabolism ESF0.3510.146
  • Hepatic transport processes are predicted with SCHHs, whereas metabolic rates are predicted with suspended hepatocytes (in vitro metabolic rates: human hepatocytes, 234.6 pmol/min per million; monkey hepatocytes, 798 pmol/min per million). ESF, empirical scaling factor.

  • a CLliver,pass, kliver,uptake, and kliver,metabolism provided in this table are calculated as the product of hepatocyte clearance (or rate, Table 1) and physiologic scaling factors (i.e., tissue weight and hepatocytes per gram of liver), without ESF. Values for hepatocytes per gram of liver are 120, 122, and 108 million for humans, monkeys, and rats.

  • b Prospective ESF is approximated using published values after accounting for different binding values between publications and this study (see details in the Materials and Methods).

  • c Retrospective ESF is calculated as the ratio of clearance (or rate) estimated by fitting in vivo data (Table 3) to the physiologically predicted clearance (or rate) in this table.

  • d For rats, we only provide IVIVE ratio for uptake, due to high uncertainty associated with other parameters in fitting rat in vivo data.