HEPATIC FUNCTION
Arthur J. Atkinson, Jr., M.D., Darrell R. Abernethy, M.D., Ph.D., Charles E. Daniels, R.Ph., Ph.D., FASHP, Robert L. Dedrick, Ph.D., and
Sanford P. Markey, Ph.D. Principles of Clinical Pharmacology
Roger K. Verbeeck, Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction
The Liver
• The liver is the most important organ for structural alteration and
disposal of drugs, generating metabolites which may be biologically
active or inactive (or toxic)
• Orally administered drugs absorbed from the gastrointestinal tract,
pass through the liver to the systemic circulation, rendering the liver
vulnerable to injury from chemicals and drugs
• Conversely, disordered hepatic function is an important cause of
abnormal drug handling and responses
The Liver
Hepatocytes are the main cell tissue of the liver (70-85%)
These cells are involved in:
• Detoxification, modification, and excretion of exogenous and
endogenous substances
• Protein synthesis and storage
• Transformation of carbohydrates
• Synthesis of cholesterol, bile salts and phospholipids
• The hepatocyte also initiates formation and secretion of bile.
Metabolism
Processes in the liver can be biochemically classified as:
• Phase I reactions (oxidation) – Addition of functional groups to render
drug inactive
• Phase II (conjugation reactions e.g. glucuronidation) – Addition of
groups to create polar metabolites for urinary excretion
CYP450 enzymes are mainly responsible for these reactions.
CYP3A4, CYP2C9, CYP2C19 & CYP2D6 have the greatest impact on
metabolism – genetic variants can lead to ‘’poor metabolisers’’ and need
to be treated as covariates when modelling
T.P. Kenakin, A Pharmacology Primer, 2009, p193
Hepatic blood flow and metabolism
• Liver blood flow (QH) is 1.35L/min
• Complex changes in blood flow occur with liver disease
Hepatic Extraction Ratio (EH)
Cin
Cout
EH
The hepatic extraction ratio can be viewed as the measure of the organ's
relative efficiency in eliminating the drug from the systemic circulation
over a single pass through the organ.
Cout
EH  1 
Cin
e.g. an EH of 0.8 means only 20% of the drug leaves the liver as it enters
portal vein circulation
Hepatic Extraction Ratio (EH) and Hepatic
Clearance CLH
Measurement of clearance and knowledge of organ blood flow enables
calculation of extraction ratios:
CLH  QH  EH
where QH is the rate of hepatic blood flow.
Hepatic Clearance CLH
• EH depends on liver blood flow, the intrinsic clearance of unbound drug
(CLint), and the fraction of unbound drug in blood (fu)
fu  CLint
CLH  QH 
QH  fu  CLint
• Equation is based on the “well-stirred” or “venous equilibration” model
• Assumes that:
- liver is a single, well-stirred compartment
- drug in arterial blood entering the liver instantaneously
equilibrates with that in the venous blood
∙
Drugs and Hepatic Extraction Ratio
• Drug substances can be categorized according to the efficiency of the
liver in removing the substance from the circulation:
- High extraction ratio (EH >0.7)
fu  CLint  QH  CLH  QH
- Low extraction ratio (EH <0.3)
fu  CLint  QH  CLH  fu  CLint
- Intermediate extraction ratio (EH <0.3)
They follow the hepatic clearance equation
Nonrestrictively Metabolized Drugs (EH > 0.7)
• The hepatic clearance of these drugs is said to be bloodflow limited
and is relatively insensitive to changes in binding of drug to blood
components or enzyme/transporter activity
• Disease states associated with alterations in liver blood flow and portosystemic shunting, such as cirrhosis, will have a significant impact on
the hepatic clearance of these drugs, especially when administered
orally.
fu  CLint  QH  CLH  QH
First Pass Metabolism
•
•
•
•
After oral administration, the
concentration of a drug, and so
the bioavailability, is greatly
reduced after it passes through
the liver
This is particularly true for the
nonrestrictively metabolized and
the intermediate extraction ratio
drugs
Drug enters the hepatic portal
system and is carried through the
portal vein into the liver before it
reaches the rest of the body
This effect is called first pass
metabolism.
First Pass Metabolism
• The fraction of an absorbed oral dose that escapes first-pass hepatic
clearance, FH, can be described by the following equation:
QH  (1  fH )  fu  CLint
FH  1  fH  EH 
QH  fu  CLint
where fH is the fraction of the mesenteric blood flow passing through
the functioning liver.
• Disease may lead to porto-systemic shunts (reduction in fH) and
decreased activity of a number of important drug-metabolizing
enzymes (reduction in CLint ), which will result in a substantial increase
in the bioavailability of orally administered flow-limited drugs.
Restrictively Metabolized Drugs (EH < 0.3)
• The hepatic clearance of poorly extracted drugs is mainly influenced
by changes in blood/plasma binding and the intrinsic hepatic clearance
and is considered to be enzyme/transporter-capacity limited.
fu  CLint  QH  CLH  fu  CLint
Oral and Intravenous Clearance
• Assuming that a drug is completely and exclusively eliminated by
hepatic mechanisms and that all of the orally administered dose is
absorbed into the intestinal epithelial cells from where it will pass into
the portal circulation, it can be shown that the oral clearance is
described by the following equation
Dor
CLor 
 fu  CLint
AUC 0  
• This means that irrespective of its hepatic extraction efficiency, the oral
clearance of a drug is determined by its degree of binding to
blood/plasma components and the intrinsic clearance of the
elimination/transport process.
• Oral doses of nonrestrictively metabolized drugs should not need to be
adjusted in response to changes in hepatic blood flow.
Oral and Intravenous Clearance
• For drugs administered intravenously, assuming that they are
completely and exclusively eliminated by the liver, the intravenous or
systemic clearance is mainly determined by the equation for
clearance, considering their extraction ratio.
• However, in both cases, we should consider that renal excretion
contributes to drug elimination. For example, it could reduce AUCor
and lead to overestimation of fuCLint
Biliary Excretion of Drugs
• Many polar drug metabolites, such as glucuronide conjugates, undergo
biliary excretion
• In order for compounds to be excreted in bile they must first pass the
fenestrated endothelium that lines the hepatic sinusoids, then cross
both the luminal and canalicular membrane surfaces of hepatocytes.
• Passage across these two hepatocyte membrane surfaces often is
facilitated by active transport systems
• Route of administration may also influence the extent of drug excretion
into bile. Oral administration may cause a drug to be extracted by the
liver and excreted into bile to a greater degree than if the intravenous
route were used.
Biliary Excretion of Drugs
• Drugs excreted into bile traverse the biliary tract to reach the small
intestine, where they may be reabsorbed.
• Drug metabolites that reach the intestine also may be converted back
to the parent drug and be reabsorbed.
• The term enterohepatic circulation refers to this cycle in which a drug or
metabolite is excreted in bile and then reabsorbed from the intestine
either as the metabolite or after conversion back to the parent drug.
• Enterohepatic cycling of a drug increases its bioavailability and
prolongs its elimination-phase half-life.
Biliary Excretion of Drugs
•
•
Enterohepatic circulation may result in a
second peak in the plasma level.
The occurrence of this large peak of drug
concentration in intestinal fluid appears to
reflect intermittent gallbladder contraction
and pulsatile delivery of drug-containing
bile to the intestine, because this doublepeak phenomenon is not encountered in
animal species that lack a gallbladder
Biliary Excretion of Drugs
•
•
Realistic pharmacokinetic modelling of this
process entails incorporation of a variable
lag-time interval that can reflect
intermittent gallbladder emptying
Drug enters the gallbladder via the liver,
for which a separate compartment is not
required, either during first-pass transit
from the gut via the portal circulation (k1)
or directly from the systemic circulation
(k2). The irregular discharge of drug
containing bile from the gallbladder is
indicated by the arrow going from
gallbladder (GB) to gut. Drug distribution
within the body is modelled as a twocompartment system.
Hepatocyte assays to measure Hepatic
Metabolism of Drugs
Advantages:
• Physiologically relevant
• Contains all enzymes drug will encounter during first pass
• Exposure to relevant transporters
• Higher published correlations with in vivo clearance data
Limitations:
• Can give incorrect data when phase II conjugation or active reuptake
predominates
• Low throughput