Hepatic Clearance

Submitted By: Submitted To:

Abdullah Al Mahmud (171-037-032) Fahrima Islam Tanji
Lecturer
Department of Pharmacy
Primeasia University
 Content
• Hepatic clearance
• First-pass metabolism
• Organ clearance
• Liver Extraction ratio
• Relationship between Absolute Bioavailability
and Liver Extraction
• Relationship between Blood Flow, Intrinsic
• Clearance, and Hepatic Clearance
• Variation in intrinsic clearance
• Biliary Drug Excretion
Hepatic Clearance
• Hepatic
  clearance may be defined as the volume of blood
that perfuses the liver and is cleared of drug per unit of time.
• Total body clearance is composed of all the clearances in the
body.
ClCl+Cl
Where ,
• Clis total body clearance.
• Clis nonrenal clearance.
• Clis renal clearance
First Pass Effect
• The first pass effect (also known
as first-pass metabolism or
presystemic metabolism) is a
phenomenon of
drug metabolism whereby the
concentration of a drug, specifically
when administered orally, is greatly
reduced before it reaches the
systemic circulation.
First Pass Effect
• To overcome first-pass effect, the route of administration of the
drug may be changed.
• For example, nitroglycerin may be given sublingually or topically,
and xylocaine may be given parenterally to avoid the first-
passeffects.
• Another way to overcome first-pass effects is to either enlarge the
dose or change the drug product to a more rapidly absorbable
dosage form.
 Physiologic/Organ Clearance
• Clearance is the product of the blood flow (Q) to Q Ca Q Cv
Elimination
the organ, and the extraction ratio (ER). The ER Organ
is the fraction of drug extracted by the organ
asdrug passes through.
• If the drug concentration in the blood (Ca)
entering the organ is greater than the drug
concentration of blood (Cv) leaving the organ, Elimination Drug
then some of the drug has been extracted by the
organ.
Q= Blood Flow
Ca= Incoming Drug Concentration
Cv= Outgoing Drug Concentration
Liver Extraction Ratio
•  
The liver extraction ratio (ER) provides a direct measurement of drug removal
from the liver after oral administration of a drug.
ER
• For example, for propranolol, ER or [E] is about 0.7—that is, about 70% of the drug
is actually removed by the liver before it is available for general distribution to the
body.
Drug Extraction Ratio
Low (<0.3) High (>0.7)
Antipyrine Lidocain
Diazepam Meperidine
Phenylbutazone Proproxyphene
Theophylline Propranolol
Tolbutamide Verapamil
Warfarin

Intermediate: Quinidine
Factors That Affect Hepatic Clearance of Drug

• Blood flow
• Intrinsic clearance
• The fraction of the drug bound in protein
Relationship between Blood Flow, Intrinsic
Clearance and Hepatic Clearance
• Blood flow: Blood flow refers to the movement
of blood through a vessel, tissue, or organ, and is
usually expressed in terms of volume of blood per
unit of time.
• Propranolol, a β-adrenergic blocking agent,
decreases hepatic blood flow by decreasing
cardiac output. In such a case, the drug decreases
its own clearance through the liver when given
orally.
Relationship between Blood Flow, Intrinsic
Clearance and Hepatic Clearance
•  
Hepatic clearance is a concept for characterizing drug elimination based on both
blood flow and the intrinsic clearance of the liver, as shown in equation,
Cl󠇇=Q
• Intrinsic clearance (Clint) describes the total ability of the liver to metabolize a drug
independently of blood flow.
• Intrinsic drug clearance primarily occurs because of inherent ability of the
biotransformation enzymes (mixed-function oxidases) to metabolized the drug as it
enters the liver.
• Levels of these enzymes are increased by various drugs (e.g, phenobarbital) and
environmental agents (e.g, tobacco smoke).
• These enzymes are inhibited by other drugs and environmental agents (e.g, cimetidine,
acute lead poisoning)
Sources of Variation in Intrinsic Clearance

• Genetic factors.
• Genetic differences within population.
• Racial differences among different population.
• Environmental factors and drug interactions:
• Enzyme induction.
• Enzyme inhibition
Physiological Conditions
• Age.
• Gender.
• Diet / Nutrition.
• Pathophysiology.
• Drug dosage regimen.
• Route of drug administration
Biliary Excretion
• Biliary excretion involves active secretion of drug
molecules or their metabolites from hepatocytes
into the bile.
• Some drugs are absorbed from GIT through the
mesenteric and hepatic portal veins, proceeding
to the liver.
• The liver may secrete some of the drug
(unchanged or as a glucuronide metabolite) into
the bile.
• From the bile (stored in the gallbladder), the drug
may empty into the GIT through the bile duct.
Conclusion