Download One Compartment Models - Shenandoah University

Hepatic Clearance/1st Pass
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Liver overview
Hepatic clearance
Hepatic extraction ratio
Bioavailability and first pass metabolism
Enterohepatic recirculation
Question
• One drug a patient is taking is metabolized
by CYP3A4 and the patient starts taking
erythromycin (a CYP3A4 enzyme
inhibitor), will the hepatic clearance of the
first be altered?
Liver
• about 1500g
• 50-100k lobules
• blood flow: 10001500 ml/min
• metabolizes drugs
• excretes drugs into
the bile
Intestine
Liver Structure
Hepatocyte Drug Metabolism
albumin
Smooth ER
Clearance
CLH  Q * ER
• Liver blood flow (Q or LBF) normally ranges
between 1000-1500 mL/min or 60-90 L/hr
• If asked to use in a calculation, we will use the
mean of 1250 mL/min or 75 L/hr for normal liver
blood flow
Clearance
CLH  Q * ER
Extraction ratio (ER) is a measure of efficiency
of the liver at removing the drug from the
bloodstream. It is highly variable and
dependent on three factors:
– intrinsic clearance (CLint) of the liver for the
particular drug
– fraction of the drug unbound (fup)
– blood flow (Q)
How to Calculate ER
• If you can’t find ER directly, it can be
calculate from other information that can
be easily looked up for a particular drug:
CLT and fe.
CLH (1 - fe) * CLT
ER 

Q
Q
Examples
• CLT = 1400 ml/min and fe = 0.2
• CLT = 300 ml/min and fe = 0.8
Classification of ER
• ER > 0.7
A “high ER” drug and therefore the liver is
very efficient at removing the drug
• 0.3 < ER < 0.7
An “intermediate or moderate ER” drug and
therefore the liver is moderately efficient at
removing the drug
• ER < 0.3
A “low ER” drug and therefore the liver is not
efficient at removing the drug
Hepatic Extraction Ratio
ER 
f up * CLint
Q  f up * CLint
• fup - fraction of the drug unbound
• CLint - intrinsic clearance
• Q - blood flow
Hepatic Clearance
CLH  Q * ER
ER 
CL H 
f up * CLint
Q  f up * CLint
Q * f up * CLint
Q  f up * CLint
Venous Equilibration Model
This equation can be simplified to see the
determinants of hepatic clearance for low
and high ER drugs individually.
CL H 
Q  f up  CLint
Q  f up  CLint
Low ER
By definition a low ER drug has a ER < 0.3
and therefore the liver is inefficient at
removing the drug from the blood.
f up  CLint  Q
CL H 
Q  f up  CLint
Q  f up  CLint
Low ER
So the denominator of the VE equation can
be reduced to Q:
CLH 
Q  f up  CLint
Q
Simplified equation for low ER drugs
CL H  f up  CLint
High ER
By definition a high ER drug has a ER > 0.7
and therefore the liver is very efficient at
removing the drug from the blood.
f up  CLint  Q
CL H 
Q  f up  CLint
Q  f up  CLint
High ER
So the denominator of the VE equation can
be reduced to fup*CLint:
CLH 
Q  f up  CLint
f up  CLint
Simplified equation for high ER drugs
CLH  Q
Determinants of Hepatic
Clearance
• For any drug?
• For low ER drugs?
• For high ER drugs?
Alterations in the Determinants
Clearance intrinsic (CLint)
• Enzyme inducers increase the number of enzymes
in the liver thus increasing Vmax, so CLint will
increase.
• Enzyme inhibitors in general competitively
compete with the other drug for the same enzyme
receptor. Therefore, the apparent Km is increased
and CLint will decrease.
• Liver disease can also produce a decrease in Vmax
from tissue destruction thereby causing a decrease
in CLint.
Alterations in the Determinants
Protein binding (fup)
• Highly bound drugs can be displaced from protein
binding sites by other drugs or other substances
which will increase the fup
• Alterations in the amount of the protein the drug is
bound to will also change the fup
– Malnutrition can cause decreases in albumin
and therefore an increase in fup
– Acute myocardial infarction can cause and
increase in AAG and decrease fup
Alterations in the Determinants
Liver Blood Flow (Q)
• Congestive Heart Failure (CHF) will
decrease Q
• Food (especially high fat meals will cause a
transient increase in Q
• Certain drugs can alter Q by changing
cardiac output
Question
• One drug a patient is taking is metabolized
by CYP3A4 and the patient starts taking
erythromycin (a CYP3A4 enzyme
inhibitor), will the hepatic clearance of the
first be altered?
Bioavailability
ORAL
DRUG
GUT
WALL
PORTAL
VEIN
SYSTEMIC
CIRCULATION
LIVER
SITE OF
ACTION
GUT
Bioavailability (F)
F  fa  F
*
fa = fraction of drug absorbed from the GI tract
F* = fraction of drug escaping first pass metabolism
F  1  ER
*
ER = hepatic extraction ratio
F  f a  (1  ER)
Bioavailability (F)
How much of a 100 mg dose will make it
into the systemic circulation if 75% of the
dose is absorbed and 40% of the drug is
removed with each pass through the liver?
Enterohepatic Recirculation
• In addition to metabolism the liver may remove
drug from the blood by excretion of parent
compound or metabolite into the bile. The bile is
then secreted into the gallbladder and periodically
released into the intestines.
• The drug can then be reabsorbed back into the
portal vein and again pass through the liver into
the systemic circulation causing a secondary peak
in the plasma concentration-time curve.
• Generally large relatively polar molecules and
examples include morphine, metoclopramide,
irinotecan, digoxin, etc.
• It is the basis for use of activated charcoal in
overdoses after drug absorption is complete
Enterohepatic Recirculation
Cmax
2° peak
Ln Cp
time