Scaling factor, metabolic clearance

The drawback of this approach is that it is essentially empirical, and does not allow for differences in metabolic clearance between the species, i.e., it assumes that clearance is proportional to blood flow. This works well for compounds that are highly extracted in the liver, and/or where passive renal clearance is the major pathway [5, 68]. An approach for compounds that are actively secreted into the urine has also been proposed [69], although the precise values of some of the physiological scaling factors have been questioned [70]. 

Obach et al. [27] proposed a model to predict human bioavailability from a retrospective study of in vitro metabolism and in vivo animal pharmacokinetic (PK) data. While their model yielded acceptable predictions (within a factor of 2) for an expansive group of compounds, it relied extensively on in vivo animal PK data for interspecies scaling in order to estimate human PK parameters. Animal data are more time-consuming and costly to obtain than are permeability and metabolic clearance data hence, this approach may be limited to the later stages of discovery support when the numbers of compounds being evaluated are fewer. 

Carlile DJ, Zomorodi K, Houston JB. 1997. Scaling factors to relate drug metabolic clearance in hepatic microsomes, isolated hepatocytes, and the intact liver studies with induced livers involving diazepam. Drug Metab Dispos 25 903-911. 

Because Vmax - m can be obtained from in vitro metabolism experiments, development scientists may reasonably predict the in vivo clearance parameter of a low or intermediate extraction ratio drug from in vitro data, by use of Equations 17.13 and 17.17. By use of appropriate scaling factors, the in vivo clearance parameter in humans can be ap-... 

Barter ZE, Bayliss MK, Beaune PH, Boobis AR, CarUle DJ, Edwards RJ, Houston JB, Lake BG, Lipscomb JC, Pelkonen OR, Tucker GT, Rostami-Hodjegan A. Scaling factors for the extrapolation of in vivo metabolic drug clearance from in vitro data Reaching a consensus on values of human microsomal protein and hepatoceUularity per gram of liver. Curr Drug Metab 2007 8(1) 33—45. 

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