DISTRIBUTION
The body is a container in which a drug is distributed by
blood (different flow to different organs) - but the body is not
homogeneous.
Factors affecting drug delivery from the plasma:
A- blood flow: kidney and liver higher than skeletal muscles and
adipose tissues.
B- capillary permeability:
1- capillary structure: blood brain barrier
2- drug structure
C- binding of drugs to plasma proteins and tissue proteins
Apparent Volume of Distribution
Vd = Amount of drug in the body
Plasma drug concentration
VD = Dose/Plasma Concentration
 It is hypothetical volume of fluid in which the drug is
disseminated.
 Units: L and L/Kg
 We consider the volume of fluid in the body = 60% of BW
 60 X 70/100 = 42 L
Drug Distribution
Water Body Compartments
• Drugs may distribute into
•




Plasma (Vascular) Compartment:
Too large mol wt
Extensive plasma protein binding
Heparin is an example
Extracellular Fluid
 Low mol wt drugs able to move via endothelial
slits to interstitial water
 Hydrophilic drugs cannot cross cell membrane to
the intracellular water
Plasma
(4 litres)
Interstitial Fluid
(11 litres)
Intracellular Fluid
(28 litres)
 Total Body Water; Low mol wt
hydrophobic drugs distribute from
interstitial water to intracellular
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Plasma
Compartment
Extracellular
Compartment
Drug has large Mol. Wt.
OR
Bind extensively to pp
Drug has low Mol. Wt.
Hydrophilic
Distributed in plasma &
Interstitial fluid
Vd = 4L
6% of BW
e.g. Heparin
Vd = 14L
21% of BW
e.g. Aminoglycosides
Intracellular
Compartment
Drug has low Mol. Wt.
Hydrophobic
Distributed in three comp.
Accumulated in fat
Pass BBB
Vd= 42L
60% of BW
e.g. Ethanol
Plasma protein binding
 Many drugs bind reversibly to plasma proteins especially albumin
 D + Albumin↔ D-Albumin (Inactive) + Free D
 Only free drug can distribute, binds to receptors, metabolized and
excreted.
Clinical Significance of Albumin Biding
 Class I: dose < available albumin binding
sites (most drugs)
 Class II: dose > albumin binding sites
(e.g., sulfonamide)
• Drugs of class II displace Class I drug
molecules from binding sites→ more
therapeutic/toxic effect
Sulfonamide
• In some disease states → change of
plasma protein binding
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 In uremic patients, plasma protein binding
to acidic drugs is reduced
• Plasma protein binding prolongs duration
Displacement of Class-I
Drug
Alter plasma binding of drugs
1000 molecules
999
% bound
900
1
molecules free
100
100-fold increase in free pharmacologically
active concentration at site of action.
Effective
TOXIC
• Capillary permeability
 Endothelial cells of capillaries in Liver capillary
tissues other than brain have wide slit
junctions allowing easy movement of
drugs
Slit junctions
 Brain capillaries have no slits between
endothelial cells, i.e tight junction or Brain capillary
blood brain barrier
Glial cell
 Only carrier-mediated transport or
highly lipophilic drugs enter CNS
 Ionised or hydrophilic drugs can’t get
Tight junctions
into the brain
Endothelial cells
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Barriers to Drug Distribution
Blood-Brain barrier:
Inflammation
during meningitis or
encephalitis may increase permeability into
the BBB of ionised & lipid-insoluble drugs
Placental Barrier:
Drugs that cross this barrier reaches fetal
circulation
Placental barrier is similar to BBB where only
lipophilic drugs can cross placental barrier
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Metabolism
• It is enzyme catalyzed conversion of drugs to their
metabolites.
• Process by which the drug is altered and broken down
into smaller substances (metabolites) that are usually
inactive.
• Lipid-soluble drugs become more water soluble, so
they may be more readily excreted.
• Most of drug biotransformation takes place in
the liver, but drug metabolizing enzymes are
found in many other tissues, including the gut,
kidneys, brain, lungs and skin.
• Metabolism aims to detoxify the substance
but may activate some drugs (pro-drugs).
•
Reactions of Drug Metabolism
Phase I
Conversion of
Lipophyllic molecules
Into
more polar molecules
by
oxidation, reduction and hydrolysis
reactions
↑↓or unchanged
Pharmacological
Activity
Phase II
Conjugation with certain substrate
Inactive compounds
Phase I Biotransformation
• Oxidative reactions: Catalyzed mainly by family of enzymes;
microsomal cytochrome P450 (CYP) monoxygenase system.
Drug + O2 + NADPH + H+ → Drugmodified + H2O + NADP+
• Many CYP isoenzymes have been identified, each one responsible for
metabolism of specific drugs. At least there are 3 CYP families and
each one has subfamilies e.g. CYP3A.
• Many drugs alter drug metabolism by inhibiting (e.g. cimetidine) or
inducing CYP enzymes (e.g. phenobarbital & rifampin).
• Pharmacogenomics
Phase I Biotransformation (continue)
• Oxidative reactions: A few drugs are oxidised by cytoplasmic enzymes.
– Ethanol is oxidized by alcohol dehydrogenase
– Caffeine and theophylline are metabolized by xanthine oxidase
– Monoamine oxidase
• Hydrolytic reactions: Esters and amides are hydrolyzed by:
– Cholineesterase
• Reductive reactions: It is less common.
– Hepatic nitro reductase (chloramphenicol)
– Glutathione-organic nitrate reductase (NTG)
Phase II Biotransformation
• Drug molecules undergo conjugation reactions with an endogenous
substrate such as acetate, glucuronate, sulfate or glycine to form watersoluble metabolites.
• Except for microsomal glucuronosyltransferase, these enzyems are located
in cytoplasm.
• Most conjugated drug metabolites are pharmacologically inactive.
– Glucuronide formation: The most common using a glucuronate
molecule.
– Acetylation by N-acetyltransferase that utilizes acetyl-Co-A as acetate
donar.
– Sulfation by sulfotransferase. Sulfation of minoxidil and triamterene
are active drugs.
LONGITUDNAL SECTION OF KIDNEY
09-12-2010
KLECOP, Nipani
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