DrugTheGuide
Pharmacokinetics

Extraction Ratio ER

The fraction of drug removed from the blood during a single pass through an eliminating organ — a key determinant of first-pass bioavailability and how liver disease alters drug clearance.

Definition and Formula

The extraction ratio (ER) is defined as the fraction of drug removed from blood during passage through the eliminating organ:

ER = (Cin − Cout) / Cin

From this, hepatic clearance (CLH) follows the well-stirred (venous equilibrium) model:

CLH = QH × ER = QH × fu × CLint / (QH + fu × CLint)

Where QH = hepatic blood flow (~1.5 L/min), fu = unbound fraction in blood, and CLint = intrinsic clearance (enzyme capacity). Background: NCBI StatPearls pharmacokinetics ↗, PubMed: hepatic ER reviews ↗.

High, Intermediate, and Low Extraction Drugs

High ER (> 0.7)

Flow-limited clearance. Extensive first-pass — poor oral bioavailability. Clearance sensitive to changes in hepatic blood flow.

Examples: lidocaine, morphine, propranolol, labetalol, verapamil, isoproterenol, nitroglycerin

Intermediate ER (0.3–0.7)

Both blood flow and enzyme capacity contribute to clearance. Moderate first-pass effect.

Examples: aspirin, codeine, nortriptyline, quinidine

Low ER (< 0.3)

Capacity-limited clearance. Good oral bioavailability. Clearance sensitive to enzyme activity and protein binding changes.

Examples: warfarin, diazepam, phenytoin, theophylline, tolbutamide

Extraction Ratio and Oral Bioavailability

For drugs absorbed via the gut and passing through the liver before reaching systemic circulation, oral bioavailability (F) is directly limited by the hepatic extraction ratio:

Fhepatic = 1 − ER

For morphine (ER ≈ 0.85): F ≈ 15–25% — which is why oral morphine doses are 3× higher than IV doses. For propranolol (ER ≈ 0.75): F ≈ 25%. This first-pass effect is the reason high-ER drugs often have very different oral vs parenteral dose requirements.

Important: gut wall metabolism and intestinal CYP3A4 activity also contribute to overall first-pass effect in addition to hepatic ER. Full first-pass bioavailability: F = Fgut × Fhepatic = Fgut × (1 − ER). See our drug metabolism guide.

Clinical Implications

  • Liver disease and high-ER drugs: Portal hypertension reduces hepatic blood flow and creates portosystemic shunts that bypass the liver — oral high-ER drugs (morphine, propranolol) reach systemic circulation largely unmetabolised, dramatically increasing exposure. See hepatic dosing guide and FDA hepatic impairment guidance ↗.
  • CYP inhibitors and low-ER drugs: For low-ER, capacity-limited drugs (warfarin, phenytoin), CYP inhibition directly reduces CLint and increases plasma concentrations — sometimes dramatically. See CYP450 guide.
  • Sublingual/transdermal routes: These bypass hepatic first-pass entirely — particularly important for high-ER drugs. Sublingual nitroglycerin has near-complete bioavailability despite high ER.
  • IV vs oral dose equivalences: When switching from IV to oral for high-ER drugs, the oral dose must be substantially higher. Standard conversion tables for opioids (morphine, oxycodone) and antiarrhythmics reflect this. See DailyMed ↗ prescribing information.

FAQ

What is the extraction ratio?
The extraction ratio (ER) is the fraction of a drug removed from the blood during a single pass through an eliminating organ (usually the liver). ER = (Cin − Cout) / Cin, where Cin is the drug concentration entering the organ and Cout is the concentration leaving. ER ranges from 0 (no extraction) to 1 (complete extraction).
What is the difference between high and low extraction ratio drugs?
High extraction ratio drugs (ER > 0.7, e.g. lidocaine, morphine, propranolol) are efficiently cleared by the liver; their hepatic clearance is limited by blood flow (flow-limited). Low extraction ratio drugs (ER < 0.3, e.g. warfarin, diazepam, phenytoin) have clearance limited by intrinsic enzyme capacity and protein binding (capacity-limited). Intermediate extraction drugs fall between 0.3–0.7.
Why do high extraction ratio drugs have poor oral bioavailability?
High extraction ratio drugs undergo extensive first-pass metabolism — most of the absorbed drug is removed by the liver before reaching systemic circulation. For a drug with ER = 0.9, only 10% of an oral dose reaches the systemic circulation (F = 1 − ER = 0.1). This is why morphine, lidocaine, and propranolol are poorly bioavailable orally or require much higher oral doses than IV doses.
How does liver disease affect high vs low ER drugs differently?
High ER drugs: liver disease reduces hepatic blood flow (via portal hypertension and portosystemic shunting), dramatically reducing first-pass clearance and increasing oral bioavailability by 2–5-fold. This is the most dangerous scenario — dose must be reduced substantially. Low ER drugs: clearance depends on intrinsic enzyme activity and protein binding; cirrhosis reduces CYP enzyme expression and albumin synthesis, requiring dose adjustment but through a different mechanism.