#Hepatic clearance

#Define clearance and hepatic extraction ratio

Clearance is the hypothetical volume of plasma from which a drug is completely removed per unit time. It reflects the efficiency of elimination, not the amount removed.

Total body clearance is the sum of clearance by all elimination pathways, including:

• Renal clearance
• Hepatic clearance
• Other organ clearance (e.g. lung, gut wall)
• Non-organ dependent clearance (e.g. plasma esterases, spontaneous degradation)

Hepatic clearance ($Cl_H$) is the volume of drug cleared by the liver per unit of time.

Hepatic extraction ratio ($E_H$) is the fraction of drug presented to the liver that is cleared in a single pass. It depends on:

• Unbound fraction of drug ($f_u$)
• Intrinsic clearance ($Cl_{int}$), reflecting hepatic enzyme activity
• Hepatic blood flow
• Mathematically, $E_H = (f_u × Cl_\text{{int}}) / (\text{HBF} + f_u × Cl_\text{{int}})$

The relationship between hepatic clearance, extraction and hepatic blood flow (HBF) can be expressed as:

$$Cl_H = \text{HBF} × E_H$$

#Describe the role of the liver in drug clearance with examples

#Determinants of hepatic clearance

#Hepatic blood flow

The hepatic clearance equation shows us that a reduction in hepatic blood flow decreases hepatic drug clearance, while an increase in hepatic blood flow increases drug clearance. This effect is most pronounced for drugs with a high extraction ratio (e.g. propofol). For these drugs, extraction is already efficient so blood flow becomes the limiting factor for drug clearance.

Reduced hepatic blood flow also increases the hepatic extraction ratio. This can be thought of as the concentration of hepatic enzyme activity on a smaller volume of blood, leading to greater proportion of the drug being cleared. This effect will not overcome the overall decrease in hepatic clearance described above.

#Intrinsic clearance

• Reflects hepatic enzyme activity and capacity
• Greater activity → greater clearance
• Enzyme activity may be affected by:
  • hyper- or hypothermia
  • acidosis or alkalosis
  • inhibition, induction or competition for metabolic enzymes (e.g. CYP450)

#Protein binding

• Only the unbound drug fraction of the drug is available for metabolism
• The unbound fraction increases when there is less protein binding, for example due to:
  • low serum protein
  • competition with other highly protein bound drugs (e.g. phenytoin)

#High vs low extraction ratio

#High extraction ratio drugs ($E_H$ > ~0.7)

For drugs with high extraction ratio (e.g. propofol), clearance is flow-limited.

• Clearance is already efficient. If more blood were presented to the liver, it would be able to clear more.
• Hence drugs with high extraction ratio are more sensitive to blood flow.
• Conversely, they are relatively insensitive to changes in enzyme activity or protein binding as nearly all drug delivered to the liver is eliminated anyway

#Low extraction ratio drugs ($E_H$ < ~0.3)

For drugs with low extraction ratio (e.g. diazepam), clearance is capacity-limited.

• Clearance is not very efficient. Delivery of more blood to the liver will not significantly improve clearance.
• Hence clearance depends mainly on intrinsic clearance and protein binding, and is less affected by hepatic blood flow

#Implications for bioavailability

First-pass metabolism occurs when orally administered drugs pass through the liver before reaching systemic circulation.

Increased hepatic clearance therefore decreases the bioavailabillity of orally administered drugs.

#Metabolic pathways: Phase I, II and III reactions

#Phase I reactions (functionalisation)

• Often the first metabolic step, primarily mediated by cytochrome P450 enzymes.
• Involves the addition of exposure of polar functional groups (e.g. amino or hydroxyl groups)
• Effect:
  • Produces molecules that are generally more water soluble than their predecessors, which are more easily eliminated by the kidneys.
  • Prepares the drug for phase II reactions (conjugation).
  • This process may produce active, inactive, or toxic metabolites.
• There are three types of phase I reactions:
  • Oxidation
    • e.g. Diazepam → oxazepam / temazepam
    • e.g. thiopentone
  • Reduction, e.g. warfarin
  • Hydrolysis, e.g. lignocaine by hepatic amidases

#Phase II reactions (conjugation)

• Conjugation with endogenous substrates.
• Usually (but not always) produces inactive, water soluble metabolites.
• Water soluble metabolites are more easily eliminated by the kidneys.
• Many drugs undergo multiple conjugation reactions.

Examples

• Glucuronidation: Paracetamol
• Sulfation: Propofol
• Acetylation: Dantrolene, hydralazine, alfentanil
• Methylation: Catecholamines (via COMT), dobutamine
• Glutathione conjugation: NAPQI (toxic paracetamol metabolite)
• Amino acid conjugation: various drugs and endogenous compounds

#Phase III reactions

Drugs may undergo additional modification before active transport into biliary ducts and elimination via bowel.