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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. This value of F combines the total fraction absorbed, fraction escaping intestinal and first-pass metabolism. 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

Child model only

A checkbox has been provided to specify whether the apparent clearance pertains to an adult. If the checkbox is selected, the system interprets the input as an adult value and calculates the corresponding apparent clearance for children (CLchild) using the scaling equations as follows:3

CLchild= CLadult × ( BWchild / BWadult) 0.75

where CLadult is the apparent clearance of adult, BWchild and BWadult are body weights of a child and an average adult (70 kg) respectively.

⋇ Intrinsic

Intrinsic inputs
Gut

The intrinsic clearance of gut (CLint,gut) is calculated for CYP3A enzymes using the following equation:4

CLint, gut (L/h) = CLint, CYP3A (in uL/min/pmol) × CYP3A Abundance (nmol) × (unit conversion to L/h)

where CLint, CYP3A is the total intrinsic clearance of CYP3A enzymes for any given drug and the total abundance of CYP3A in the intestine is 70.5 nmol. 4,5

Hepatic

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

where,

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

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

CLapp = Σ CLint, enzymes

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
  3. Johnson TN, Rostami-Hodjegan A, Tucker GT. Prediction of the Clearance of Eleven Drugs and Associated Variability in Neonates, Infants and Children. Clinical Pharmacokinetics. 2006 2006/09/01;45(9):931-56. https://doi.org/10.2165/00003088-200645090-00005.
  4. Paine MF, Khalighi M, Fisher JM, Shen DD, Kunze KL, Marsh CL, et al. Characterization of interintestinal and intraintestinal variations in human CYP3A-dependent metabolism. J Pharmacol Exp Ther. 1997;283(3):1552-62. https://www.ncbi.nlm.nih.gov/pubmed/9400033.
  5. Gertz M, Harrison A, Houston JB, Galetin A. Prediction of human intestinal first-pass metabolism of 25 CYP3A substrates from in vitro clearance and permeability data. Drug Metab Dispos. 2010;38(7):1147-58. https://doi.org/10.1124/dmd.110.032649.