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Clearance

CL inputs

Currently, the model supports apparent and intrinsic clearance as inputs.

⋇ Apparent

Apparent clearance (CL/F) should be entered here and the equation computing the hepatic clearance is shown below in equation 1. If the value of F (absolute bioavailability) is known, please input the value in the provided box. A fraction of (1-F) from the dosed amount is removed before reaching the systemic circulation. An optional input to enter a scalar which changes the apparent clearance by the respective factor is also provided (as 'Clearance scalar') in the 'Optional inputs' tab.
Hepatic clearance (CLhep) is computed as:

CLhep= Qhv ⨯ CLapp/ (Qhv + CLapp)

where Qhv is the total blood flow through the liver and CLapp is the apparent clearance

⋇ Intrinsic

Intrinsic inputs

The model currently allows the user to select upto three metabolising enzymes (either CYPs or UGTs). Please select the drug metabolising enzymes and the appropriate in vitro intrinsic values (in µL/min/pmol or µL/min/mg) and units from provided options. The intrinsic clearance of an enzyme (CLint, enzyme) is scaled using abundance of protein in pmol/mg of microsomal protein, milligrams of microsomal protein per gram of liver1 (MPPGL) and liver weight as follows:

If CLint is in µL/min/pmol,CLint, enzyme= CLint ⨯ Enzyme Abundance (pmol/mg) ⨯ MPPGL ⨯ Liver weight

If CLint is in µL/min/mg, CLint, enzyme= CLint ⨯ MPPGL ⨯ Liver weight


Apparent clearance (CLapp) is sum of intrinsic clearances of all metabolising enzymes involved.

where,MPPGL = 101.407 + 0.0158 × Age(years) - 0.00038 × Age2 + 0.0000024 × Age3 ± 4

Hepatic clearance (CLhep) is computed using the following equation,2


CLhep= Qhv ⨯ fub ⨯ CLapp/ (Qhv + fub ⨯ CLapp)

where Qhv is total blood flow through liver, fub is unbound fraction in blood and CLapp is sum of intrinsic clearances.


References

  1. Barter ZE, Chowdry JE, Harlow JR, Snawder JE, Lipscomb JC, Rostami-Hodjegan A. Covariation of human microsomal protein per gram of liver with age: absence of influence of operator and sample storage may justify interlaboratory data pooling. Drug Metab Dispos. 2008 Dec;36(12):2405-9. https://doi.org/10.1124/dmd.108.021311
  2. Riley RJ, McGinnity DF, Austin RP. A unified model for predicting human hepatic, metabolic clearance from in vitro intrinsic clearance data in hepatocytes and microsomes. Drug Metabolism and Disposition. 2005;33(9):1304-11. https://doi.org/10.1124/dmd.105.004259