‫المحاضره السابعه‬
Liver extraction ratio:

The liver extraction ratio (ER) provides a direct measurement of
drug removed from the liver after oral administration of drug.
Ca – Cv
ER =
Ca
Where: Ca: drug conc. in blood entering the liver
Cv: drug conc. leaving liver

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
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Because Ca is usually greater than Cv.
ER is usually less than 1
Since, the sampling of drug from the hepatic portal vein and artery
is difficult.
Therefore, most ER measurements for drugs are quite in animals
which may be quite different from that in humans.
The following relationship between bioavailability and liver
extraction ratio enables a rough estimation of the extent of liver
extraction
F = 1 – ER – F''
F: is fraction of bioavailable drug
F”: is the fraction of drug removed by non-hepatic process

If F" is assumed to be negligible there is no loss of drug due to
chemical degradation, gut metabolism and incomplete absorption.
ER = 1 – F and by substitution
[AUC] 0 oral / D0 oral
ER = 1[AUC] 0 I.V. / D0 I.V
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- ER: is a rough estimation of liver extraction of drug

Factors that alter this estimation:
1) Size of dose
2) Formulation of drug
3) Pathophysiologic condition of the patients.
 Because there are many other reasons for a drug to have a
reduced F value, the extent of first-pass effects is not very
precisely measured from F value.
 The liver extraction ratio (ER) provides a direct measurement of
drug removal from the liver after oral administration of drug.
 For example:
The (ER) or (E) is about 0.7 this means that:
 About 70% of the drug is actually removed by liver
before it is available for general distribution to the
body.
 By contrast if the drug is injected I.V. most of drug would be
distributed before reaching liver and less of drug is metabolized.
Hepatic clearance (Clh):
 Is defined as a volume of blood that perfuses the liver which is
cleared of drug per unit time (5 L \ hr).
 Hepatic clearance (Clh) is also equal to total body clearance (ClT)
minus renal clearance (Clr) as following:
Clh = ClT – Clr
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 Using the average entering blood concentration Ca,
The rate of presentation of drug to the liver is = G . Ca
Where: G is the hepatic blood flow.
The rate at which drug leaves the liver is = G. CV
Where: Cv hepatic venous concentration of drug.
- The rate of elimination =
= G. Ca – G. CV = G (Ca - Cv)
- Hepatic clearance= rate of elimination/Ca
=G (Ca- Cv)/Ca
=G. ER
=hepatic blood flow ×hepatic extraction ratio
Intrinsic clearance (Cl int):
- Is used to describe the ability of liver to remove drug in the absence of
flow limitations.
 Hepatic clearance is also related to both liver blood flow &intrinsic
clearance of liver
Hepatic clearance = G (CL int /G + CL int)
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Significance of drug metabolism:
 It is important to consider what fraction of drug is eliminated by
metabolism & what fraction is eliminated by excretion.
 Drugs which are highly metabolized such as (theophylline,
lidocaine) demonstrate large variation in elimination half life's in
various people.
 Unlike renal excretion where renal excretion is relatively constant
among different people due to the constant value of glomerular
filtration rate.
 Drug metabolism is dependent on the intrinsic activity of
biotransformation enzymes which may be altered by genetic &
environmental factors.
- Estimating of reduced bioavailability due to liver metabolism
& variable blood flow:
- Blood flow to the liver play an important role in the amount of the drug
metabolized after oral administration.
 Changes in the blood flow to the liver may alter the percentage of
drug metabolized & alter the percentage of bioavailability.
 The relationship between blood flow , hepatic clearance
& percent of drug bioavailability is :
F = 1- CLh\ Q = 1- ER
Where:
CLh: is the hepatic clearance of the drug.
Q: Effective hepatic blood flow.
F: Bioavailability.
ER: Extraction ratio.
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 This equation provides a reasonable approach for evaluating
the reduced bioavailability due to first-pass metabolism effect.
 The usual effective hepatic blood flow is 1.5 L\min but may be
1 to 2 L\min depending on diet, food intake, physical activity or
drug intake.
Example:
F or drug propoxyphene hydrochloride, F was calculated (hepatic
clearance = 900 ml\min & liver blood flow = 1.53 L\min).
F = 1- ER
1- (0.9 \1.35 ) = 0.35
(ER = CLh\Q)
- This results showing that 35% of the drug is systemically
absorbed after liver extraction.
- Presystemic elimination or first pass affect is a very important
consideration for drugs that have a high extraction ratio (ER)
- Drug with low extraction ratio as theophyline, digoxin,
Diazepam, Phenobarbital, phenytoin & isoniazid have very little
presystemic elimination after oral administration (ER < 0.3).
- In contrast, drug with high extraction ratio have poor
bioavailability when given orally. EX: nitroglycerin, morphine,
propranolol & verapamil (ER > 0.7).
- Therefore the oral dose must be > I.V. dose to achieve the
same therapeutic response or use another rout of
administration such as with nitroglycerin (sublingual,
transdermal, nasal).
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 To overcome first-pass effect:
1) Route of drug administration may be changed
2) Either enlarge the dose or
3) Change the drug product to a more rapidly absorbable dosage
form.
 Effect of changing blood flow on drugs with high
and low extraction ratio:
- Drug clearance and elimination half-life are both affected by changing
blood flow to the liver.
1) For drugs with low extraction (ER = 0.1), the decrease in hepatic
blood flow from normal (1.5 L/ min) to one half  decrease
clearance only slightly and blood level of drug is slightly higher.
2) In contrast, for a drug with high extraction ratio (ER = 0.9),
decreasing blood flow to one half of normal  decreases
clearance strongly.
 Alteration in the hepatic blood flow significantly affects the
elimination of drugs with high extraction ratios (e.g. propranolol) and
have very little effect on the elimination of drugs with low extraction
ratios (e.g. theophylline).
 For low extraction ratio drugs, small changes in hepatic blood flow
do not affect the removal rate of such drugs.
 For high extraction ratios drugs, if the blood flow to the liver
decreases, the elimination is prolonged so these drugs are
considered to be flow dependent.
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 Relationship between blood flow, intrinsic clearance and
hepatic clearance.
ER = Ca – Cv / Ca
 ER: may vary from 0 to 1
 ER = 0.25 means that 25 % of the drug was removal by liver.
 If both ER and blood flow to liver are known, hepatic
clearance may be calculated by the following expression.
CLh =Q (ca - cv) / ca = Q x ER
 For some drugs as propranolol, which has high ER, by decreasing
hepatic blood flow by decreasing cardiac output, the drug decreases
its own clearance through liver when given orally.
Intrinsic clearance (Clint):
 Is used to describe the total ability of the liver to metabolize a drug in
the absence of flow limitations and reflecting the inherent activities
of mixed function oxidases and all other enzymes.
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 Hepatic clearance is concept used for characterizing drug
elimination based on both blood flow and intrinsic
clearance of liver as following:
CLh = Q (CLint / Q + CLint)
 When the blood flow to liver is constant, hepatic clearance is
equal to the product of blood flow Q and extraction ratio.
CLh= Q x ER
 Hepatic clearance of drug is not constant.
 Hepatic clearance changes with blood flow and intrinsic clearance
of drug.
 For drugs with low extraction ratio (ER) the hepatic clearance (CLh
) is less affected by hepatic blood flow (see the figure on page 9).
 These drugs are more affected by the internisic activity of mixed
function oxidases.
 Changes or alterations in mixed-function oxidase activity cause or
affect the intrinsic clearance and thus the rate of drug removal by
the liver.
 Smoking can increase the intrinsic activity (clearance) for
metabolism of many drugs.
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Increase ER, increase hepatic flow, increase hepatic
clearance.
Hepatic
1.0
Clearance
(l /min)
0.9 ER
0.8
2.5
0.7
2.0
1.5
0.6
1.0
.5
0.1
.5
1.0
1.5
2.0
2.5
Liver blood flow (L\min)
 Clearance may also be expressed as the rate of drug removed
divided by plasma drug concentration.
CLh = rate of drug removed by liver \ ca
Rate of liver Drug metabolism = CLh x Ca
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