Model Parameters

Clearance

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

⋇ IV Clearance

Intravenous clearance obtained from empirical models should be entered here and the equation computing the hepatic clearance is shown below in equation 1. If the value of F_g (fraction escaping intestinal metabolism) is known, please input the value in the provided box. A fraction of (1-F_g) from the absorbed fraction is removed before reaching the systemic circulation. An optional input to enter a scalar which changes the IV clearance by the respective factor is also provided (as 'Clearance scalar') in the 'Other Inputs' tab.
Hepatic clearance (CL_hep) is computed as:

CL_hep= Q_hv × CL_app / (Q_hv + CL_app)

where Q_hv is the total blood flow through the liver and CL_app is the apparent clearance (or) intravenous 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 (CL_child) using the scaling equations as follows:³

CL_child= CL_adult × ( BW_child / BW_adult) ^0.75

where CL_adult is the apparent clearance of adult, BW_child and BW_adult are body weights of a child and an average adult (70 kg) respectively.

⋇ Intrinsic

Gut

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

CL_{int, gut} (L/h) = CL_{int, CYP3A} (in uL/min/pmol) × CYP3A Abundance (nmol) × (unit conversion to L/h)

where CL_{int, 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 (CL_{int, 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 CL_int is in µL/min/pmol,

CL_{int, enzyme}= CL_int × Enzyme Abundance (pmol/mg) × MPPGL × Liver weight

If CL_int is in µL/min/mg,

CL_{int, enzyme}= CL_int × MPPGL × Liver weight

where,

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

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

CL_app = Σ CL_{int, enzymes}

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

CL_hep= Q_hv × fu_b × CL_app/ (Q_hv + fu_b × CL_app)

where Q_hv is total blood flow through liver, fu_b is unbound fraction in blood and CL_app is sum of intrinsic clearances.

References

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
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
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.
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.
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.