Biv / 19B15: Define clearance and HER. Describe the role of the liver in drug clearance w examples

19B15: Exam Report

Define clearance and hepatic extraction ratio (30% of marks). Describe the role of the liver in drug clearance with examples (70% of marks)

70% of candidates passed this question.

Clearance was generally well answered.

It is the volume of plasma cleared of a drug per unit time, not the mass of drug cleared. An equation was helpful in identifying the relevant components of hepatic clearance.


ClHep=QH X ERHep
ERHep= FU x ClInt / QH + FU x ClInt


QH = hepatic blood flow
ERHep = hepatic extraction ratio
FU = fraction of drug unbound in plasma
ClInt = hepatic enzymatic capacity


Many candidates did not describe the effects of hepatic blood flow and intrinsic clearance on drugs with high and low hepatic extraction ratios. Some discussion of Phase I and II reactions was also expected. 

Biv / 19B15: Define clearance and HER. Describe the role of the liver in drug clearance w examples


Clearance = volume of blood completely cleared (irreversibly removed, whether due to metabolism or excretion) of a particular drug per unit time (Units: mL/min)

Hepatic clearance

Hepatic clearance = volume of blood completely cleared by the liver per unit time

  • Hepatic Clearance = Hepatic Blood Flow x Hepatic Extraction Ratio (HER)

Hepatic Extraction ratio

Hepatic Extraction ratio = fraction of drug entering the liver which is irreversibly removed during a single pass through 


EH = \( \text{1 – } \large \frac{\text{C}_{v}}{\text{C}_{a}}  \)


  • EH = Hepatic Extraction Ratio (HER)
  • Cv = venous concentration (‘concentration out’ of the organ)
  • Ca = arterial concentration (‘concentration in’ to the organ)

Metabolism is the most important component of hepatic drug clearance -> thus hepatic extraction ratio can also be expressed with this focus in mind:


EH = \( \Large \frac{\text{fu} \times {Cl}_{int}}{\text{Q}_{H}{+fu} \times { Cl}_{int}}  \)


  • EH is the HER
  • fu is the fraction of unbound drug in the plasma/blood
  • Clint is the intrinsic clearance
  • QH is the hepatic blood flow

Hepatic extraction ratio is therefore mainly determined by:

  1. the free (unbound) fraction of the drug (which depends on plasma protein binding)
  2. the intrinsic clearance rate = the rate/ability of the liver to remove (metabolize) the drug in the absence of restrictions imposed on drug delivery to the liver cell by blood flow or protein binding.
  1. Hepatic blood flow – ↑hepatic blood flow will always ↓hepatic extraction ratio for all drugs
    • For drugs with a high intrinsic clearance, there will be minimal effect.
    • For drugs with a low intrinsic clearance, the effect will be significant

Interpretation of HER

  • HER >0.7 = high hepatic extraction ratio
  • HER <0.3 = low hepatic extraction ratio

Example Drugs

High Hepatic Extraction Ratio

  • GTN
  • Propofol
  • Verapamil

Low Hepatic Extraction Ratio

  • Diazepam
  • Warfarin
  • Phenytoin

Intrinsic clearance

Intrinsic clearance is the metabolizing power of the hepatocytes 


Clint = \( \Large \frac{\text{V}_{max}}{\text{K}_{m}}  \)


    • Intrinsic clearance = L/min
    • Vmax is the maximal rate of enzymatic reaction possible for that specific drug-enzyme interaction
      •  If the liver was presented with unlimited supplies of substrate, the enzyme system would become saturated and drug elimination would become zero-order (ie constant). The Vmax is the reaction rate at this plateau of activity.
      • Unit = mmol/min
    • Km is the Michaelis-Menten dissociation constant of the enzyme
      • It describes the affinity of the enzyme for its substrate – specifically it is the concentration of the substrate/drug required to achieve 50% of the maximum reaction rate (unit = mmol/L)

Effect of hepatic blood flow & intrinsic clearance on clearance of drugs with high vs low HER

High HER


Increased blood flow

High HER

Significant increase in clearance


Minimal increase in clearance

Increased intrinsic clearance

High HER

Minimal increase in clearance


Significant increase in clearance

Liver drug metabolic processes

Metabolism = Biotransformation = chemical modification(s) made by an organism on a chemical compound

Can be divided into two phases: Phase I & II


Phase I reactions – typically occur prior to phase II reactions for most drugs. The processes include:

  • Oxidation – Loss of electrons
    • CYP450 driven
  • Reduction – Gain of electrons.
    • CYP450 driven
  • Hydrolysis – where a water molecule ruptures one or more chemical bonds
    • Esterase driven – can be organ independent
  • CYP450 enzymes are a superfamily of enzymes that play a central role in drug metabolism
    • Examples: CYP2D6 (codeine), CYP3A4 (benzodiazepines)
    • There can be significant inter-patient variability in activity of CYP enzymes, in particular CYP2D6


Phase II reactions – involves conjugation with another compound, producing a highly polar metabolite to increase water solubility for excretion in the urine. The processes include:

  • Glucuronidation – Addition of glucuronic acid.
    • e.g. morphine, propofol
  • Sulfation – Addition of a sulfa group.
    • e.g. quinol metabolite of propofol
  • Acetylation – Addition of an acetyl group.
    • e.g. isoniazid, sulfonamides
    • Also occurs in the lung and spleen.
  • Methylation – Addition of a methyl group.
    • e.g. catecholamines
  • Conjugation with glutathione
  • Conjugation with aminoacids, e.g. taurine, glutamine, glycine

[Peck & Hill]

[Deranged physiology]

Author: Huiling Tan