HEPATIC CLEARANCE
Liver plays a major role of deforming,modifying,detoxyfying and eliminating the drugs administered orally.Any drug taken by oral route should have to first pass through the liver and there it may or may not get modified according to its pharmacological and chemical nature.
Hepatic clearance is the volume of blood plasma containing the drug cleared by the liver per unit time.
Measurement of Hepatic Clearance
It is mathematically calculated by total body clearance substracted by renal clearance as follows,
ClH =ClT -ClR
where ClH is the hepatic clearance.
In the above method the net clearance resulted from the above formula may be a rough hepatic clearance as it can be exactly defined as Nonrenal Clearance ClNR.
The exact hepatic clearance can be observed by the product of liver blood flow (Q) and the Extraction Ratio (ER) as follows,
ClH =QER.
The Extraction Ratio can be defined as the fraction of the drug that is irreversibly removed by the tissue of an organ when a portion of the plasma containing the drug perfuses through that organ tissue.
The ER is calculated by measuring the drug concentration of the plasma entering the liver and that concentration of the plasma exiting the liver.
ER = (Ca - Cv)/Ca
Values of the ER is usually ranges from 0 to 1.
For example if ER is 0.85, then 85% of the drug is removed by the liver as the plasma perfuses through the liver.If the ER is 0 then no drug is removed by the liver.
Systemic Elimination by Liver
a)By Blood Flow
Blood flow to the liver is approximately 1.5 L/Min and may be altered by exercise,food,disease or drugs.
Drugs enter the liver through the hepatic portal vein and hepatic artery and leaves through hepatic vein.
After the oral administration the drug is absorbed by the intestine into the mesenteric vessels pass into the hepatic portal vein and into the liver.From there it goes into the general circulation.
b)By Intrinsic Clearance
Intrinsic clearance states about the capacity of the liver to remove the drug independent of the blood flow.
Intrinsic clearance majorly occur due to the inherent ability of the biotransformation enzymes (mixed function oxidases) to metabolize the drug as it enters the liver.
Generally basal level mixed function oxidase enzymes biotransform drugs.
Drugs such as phenobarbital and nicotine may increase the activities of these enzymes.
On contrary drugs such as cimetidine and lead may decrease their activities.
c)By Protein Binding
Drugs bound by proteins are not cleared by liver or kidney as they cannot easily perfuse the the tissues of the organs.
Blood flow (Q) and intrinsic clearance (Clint) and free plasma concentration (f) can be related as follows,
ClH = Q*(fClint)/(Q+Clint)
Factors Affecting Hepatic Clearance
1.Changes in blood flow and inhibitors of the drug metabolism enzymes which affects the hepatic clearance of the drugs(Propranolol) that have high extraction ratios and high Clint values
2.The hepatic clearance of the drugs that have low extraction ratios and low Clint is only affected by changes in hepatic blood flow.
3.Only drugs that are highly plasma protein -bound and have a low intrinsic clearance (Phenytoin) are affected by a sudden shift in protein binding.This shift causes an increase in free-drug plasma concentration.
Biliary Drug Excretion
Biliary excretion is an active transport process in which some drugs are excreted by liver.
There are separate active systems exist for weak acids and weak bases.
1.Drugs that are generally excreted through bile are high molecular weight drugs (>500),polar drugs,such as reserpine,digoxine,and various glucuronide conjugates.
2.Recycling of drugs by enterohepatic circulation
Some drugs are absorbed from GI tract through the mesenteric and hepatic portal veins proceeds to the liver,the liver may secrete actively some drugs changed as glucuronide complexes or unchanged into the bile.
From the bile the drug may be secreted into the GI tract through the bile duct for excretion.
If the drug is a glucuronide complex the bacterial flora in the GI tract may hydrolyze the glucuronide moeity allowing the released drug to be reabsorbed.
Presystemic Elimination by First Pass
Usually most of oral drugs undergo first pass.A portion of the drug is eliminated before it enter into the systemic circulation.
1.First pass effects generally result from rapid biotransformation of the drug by liver enzymes.Other mechanism include metabolism by GI mucosal cells,intestinal flora,or biiary secretion.
2.First pass effects are usually observed by measuring the absolute bioavailability (F) of the drug.If F is < 1 that means some of the drug is eliminated before systemic absorption.
3.Drugs that have high liver extraction ratio such as propranolol shows first pass effects.
If the first pass effect is high (>90%) then either
The drug dose could be increased (Propranolol,penicillin)
The drug could be given by an alternate route.(nitroglycerin,insulin)
The dosage form could be modified (Mesalamine)
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