About the Tool

This Extraction Ratio calculator is a pharmacokinetic tool designed for students, educators, and researchers. It helps visualize how a drug’s properties interact with liver physiology to determine its rate of elimination. By understanding the hepatic extraction ratio, one can better predict how changes in blood flow or enzyme activity might affect drug clearance.

What This Calculator Does

The calculator uses the “well-stirred” model of hepatic clearance to perform several key functions:

• Calculates Hepatic Clearance (CLh): It determines the volume of blood the liver can clear of a drug per unit of time.
• Calculates Extraction Ratio (ER): It computes the fraction of the drug that is removed from the blood as it passes through the liver once.
• Classifies the Drug: Based on the ER, it categorizes the drug as having a High (>0.7), Intermediate (0.3-0.7), or Low (<0.3) extraction ratio.
• Provides Interpretation: It explains the clinical significance of the classification, indicating whether clearance is “flow-limited” or “capacity-limited.”
• Simulates Scenarios: The “What-If Analysis” feature allows you to see how changes in liver blood flow or enzyme activity (intrinsic clearance) could impact the drug’s overall clearance.

When to Use It

This educational tool is particularly useful in several contexts:

• Pharmacology Education: For students to grasp the fundamental concepts of hepatic drug metabolism and clearance.
• Understanding Drug Interactions: To model the potential impact of enzyme inducers or inhibitors on a drug’s clearance.
• Predicting Disease State Effects: To simulate how conditions that alter liver blood flow (e.g., congestive heart failure) or enzyme function (e.g., liver cirrhosis) could affect a drug’s pharmacokinetics.
• Drug Development Research: As a preliminary assessment tool for new chemical entities to predict their in vivo clearance behavior based on in vitro data.

Inputs Explained

To calculate the extraction ratio, the model requires three key parameters:

• Hepatic Blood Flow (Qh): This is the volume of blood that flows through the liver per unit of time. A typical value for a healthy adult is approximately 1500 mL/min or 90 L/hr. This value can decrease in conditions like heart failure or cirrhosis.
• Intrinsic Clearance (CLint): This represents the maximum metabolic capacity of the liver enzymes to eliminate a drug, assuming no limitations from blood flow. It is a measure of how efficiently liver enzymes (like CYP450s) can metabolize the drug.
• Fraction Unbound (fu): This is the fraction of drug in the blood that is not bound to plasma proteins (like albumin). Only the unbound drug is available to be taken up by liver cells and metabolized. The value must be between 0 (fully bound) and 1 (no binding).

Results Explained

The calculator provides two primary outputs and an interpretation:

Hepatic Clearance (CLh)

This is the calculated volume of blood cleared of the drug by the liver per unit of time. It’s the most direct measure of the liver’s efficiency in eliminating the drug.

Extraction Ratio (ER)

This is a dimensionless value between 0 and 1 (or 0% to 100%) representing the percentage of drug removed in a single pass through the liver. It’s used to classify drugs:

• High ER (> 0.7): Clearance is “flow-limited.” The liver is so efficient at metabolizing the drug that the main bottleneck is the rate at which the drug is delivered via blood flow. Changes in Qh have a large impact on clearance. Propranolol is a classic example.
• Low ER (< 0.3): Clearance is “capacity-limited.” The liver’s metabolic capacity is the bottleneck. Clearance is sensitive to changes in intrinsic clearance (enzyme activity) and fraction unbound, but not to changes in blood flow. Warfarin is a classic example.
• Intermediate ER (0.3 – 0.7): Clearance is sensitive to all three parameters: blood flow, intrinsic clearance, and fraction unbound.

Formula / Method

The calculator is based on the well-stirred (or venous equilibrium) model of hepatic clearance. The formulas used are:

Step-by-Step Example

Let’s calculate the profile for a low-extraction drug like Warfarin.

Tips + Common Errors

• Unit Consistency: Ensure that the units for Hepatic Blood Flow (Qh) and Intrinsic Clearance (CLint) are the same (e.g., both are mL/min or both are L/hr). The tool handles conversion, but it’s good practice to be mindful of this.
• Fraction Unbound (fu): Remember that fu must be a decimal fraction between 0 and 1. Do not enter a percentage (e.g., use 0.05, not 5%).
• Model Limitations: This is a simplified model. It does not account for biliary excretion, transporters, or non-uniform enzyme distribution within the liver. The results are theoretical and for educational purposes.
• “What-If” Analysis: When using the what-if sliders, remember you are entering a percentage change (e.g., -30 for a 30% decrease), not an absolute new value.

Frequently Asked Questions (FAQs)

What does “flow-limited” clearance mean for a high ER drug?

It means the rate-limiting step for drug elimination is the speed at which blood delivers the drug to the liver. The liver’s metabolic enzymes are so efficient that they can remove nearly all the drug presented to them. Therefore, increasing or decreasing liver blood flow will directly increase or decrease the drug’s clearance.

What does “capacity-limited” clearance mean for a low ER drug?

It means the rate-limiting step is the metabolic capacity of the liver enzymes themselves. The liver receives far more drug than it can process in a single pass. Therefore, clearance is sensitive to factors that change enzyme activity (inhibition/induction) or the amount of free drug available (protein binding), but is insensitive to changes in blood flow.

How does liver disease, like cirrhosis, affect hepatic clearance?

Cirrhosis can affect all three parameters. It often reduces hepatic blood flow (Qh), decreases the number of functional liver cells and enzyme activity (lowering CLint), and can reduce protein synthesis, leading to less protein binding (increasing fu). The net effect is complex but generally leads to reduced clearance and increased drug exposure.

Why is protein binding (and fu) so important for low ER drugs?

For low ER drugs, the clearance is approximately equal to `fu * CLint`. Since only the unbound drug can be metabolized, the fraction unbound (fu) is directly proportional to the clearance. A small change in protein binding (e.g., from 99% to 98% bound, which doubles fu from 0.01 to 0.02) can double the clearance of a low ER drug.

Does the extraction ratio affect a drug’s oral bioavailability?

Yes, significantly. The hepatic extraction ratio is a key determinant of the “first-pass effect.” A drug with a high ER will be extensively metabolized by the liver after being absorbed from the gut and before it reaches systemic circulation. This results in low oral bioavailability. For example, if ER is 0.8 (80%), only 20% of the absorbed dose will escape the liver and become available to the body.

How does an enzyme inhibitor affect clearance of high vs. low ER drugs?

An enzyme inhibitor decreases CLint. For a low ER drug, this will cause a proportional decrease in hepatic clearance (CLh ≈ fu * CLint). For a high ER drug, CLh is limited by blood flow (CLh ≈ Qh), so even a potent enzyme inhibitor will have little to no effect on its clearance.

How would an enzyme inducer affect clearance?

An enzyme inducer increases CLint. This would significantly increase the clearance of a low ER drug, potentially leading to therapeutic failure. It would have minimal effect on the clearance of a high ER drug.

Where do the values for CLint and fu come from?

These values are determined experimentally. Intrinsic clearance (CLint) is often measured in vitro using human liver microsomes or hepatocytes. Fraction unbound (fu) is measured by dialyzing a drug in plasma and measuring its concentration inside and outside the dialysis membrane.

References

1. Rowland, M., & Tozer, T. N. (2011). Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications (4th ed.). Lippincott Williams & Wilkins.
2. Brunton, L. L., Knollmann, B. C., & Hilal-Dandan, R. (Eds.). (2017). Goodman & Gilman’s: The Pharmacological Basis of Therapeutics (13th ed.). McGraw-Hill Education.
3. Wilkinson, G. R. (2005). Drug distribution and renal and hepatic clearance. In J. G. Hardman, L. E. Limbird, & A. G. Gilman (Eds.), Goodman & Gilman’s The Pharmacological Basis of Therapeutics (11th ed., pp. 1-32). McGraw-Hill.
4. Pang, K. S., & Rowland, M. (1977). Hepatic clearance of drugs. I. Theoretical considerations of a “well-stirred” model and a “parallel tube” model. Influence of hepatic blood flow, plasma and blood cell binding, and the hepatocellular enzymatic activity on hepatic drug clearance. Journal of Pharmacokinetics and Biopharmaceutics, 5(6), 625–653. https://doi.org/10.1007/BF01061133