Drug distribution typically refers to the process of getting pharmaceutical products from manufacturers or wholesalers to pharmacies, hospitals, clinics, or other points of dispensing. Here's an overview of how it usually works:

1. DRUG DISTRIBUTION
Asnake W.(B.Pharm, MSc in Pharmaceutics)

2. DRUG DISTRIBUTION…
 Is reversible transfer of a drug to and from the
site of measurement (blood or plasma).
 It is the passage of drug from the circulation to
the tissue and site of its action.
 Low plasma binding or high tissue binding or
high lipophilicity usually means an extensive
tissue distribution
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3. DRUG DISTRIBUTION…
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 In pharmacokinetics, the distribution is described by the
parameter V, the apparent volume of distribution.
 Volume of plasma in which the total amount of drug in the body
would be required to be dissolved in order to reflect the drug
concentration attained in plasma.
Affects
The half life of the drug and
The fluctuation of the concentration at steady
state.

4. Factors affecting drug distribution
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 Extent/rate of drug distribution
1. Membrane permeability
2. Blood perfusion
3. Lipid solubility
4. PH-PKA
5. Plasma protein binding
6. Tissue drug binding

5. Factors affecting drug distribution
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1.Membrane permeability
 Capillary walls are quite permeable
 Lipid soluble drugs pass through very rapidly
 Water soluble compounds penetrate more slowly at a
rate more dependent on their size.
Plasma membrane barrier and drug diffusion across it

6. Factors affecting drug distribution
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 There are deviations to the typical capillary structure
I. Permeability is greatly increased in the renal capillaries
- by pores in the membrane of the endothelial cells,
II. in specialized hepatic capillaries, known as sinusoids
-may lack a complete lining.
results in more extension distribution of many drugs

7. Factors affecting drug distribution
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III. Brain capillaries
 restrict the transfer of molecules from blood to brain
tissue.
 Lipid soluble compounds can be readily transferred
 This is the basis of the "blood-brain“ barrier.
Thiopental vs pencillin, Levodopa vs dopamine

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2. Blood perfusion rate
The rate at which blood perfuses to different organs varies
widely
Factors affecting drug distribution…

9. Factors affecting drug distribution…
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3.Lipid Solubility
 Lipid solubility will affect the ability of the drug to cross
lipid membrane barriers
 Very high lipid solubility can result in a drug partitioning
into highly vascular lipid-rich areas.
 these drugs slowly redistribute from body fat where they
may remain for long periods of time.

10. Factors affecting drug distribution…
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4. Effects of pH
 The rate of movement of a drug out of circulation will
depend on its degree of ionization and therefore its pKa.
 Changes in pH occurring in disease may also affect drug
distribution.
E.g. blood becomes more acidic if respiration is
inadequate.
 Barbiturate poisoning treated by Sodium bicarbonate
5.Plasma protein binding:
 Extensive plasma protein binding will cause more drug to
stay in the central blood compartment.
 ↑Strong proteinbinding=↓V

11. Blood proteins to which drugs bind
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Protein Molecular
Weight
Concentration (g%) Drugs that bind
Human Serum
Albumin
65,000 3.5-5.0 Large variety of drugs
a1-Acid
Glycoprotein
44,000 0.04-0.1 Basic drugs such as
imipramine, lidocaine,
quinidine, etc.
Lipoproteins 200,000 to
3,400,000
Variable Basic, lipophilic drugs like
chlorpromazine
a1-Globulin 59,000 0.003-0.007 Steroids like corticosterone,
and thyroxine and
cyanocobalamin
a2-Globulin 1,34,000 0.015-0.06 Vitamins A, D, E and K and
cupric ions
Haemoglobin 64,500 11-16 Phenytoin, pentobarbital, and
phenothiazines

12. Factors affecting drug distribution…
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What is the effect of protein binding on drug
action?
Extensive plasma protein binding will...decrease peak
plasma level.
 Elimination of a highly bound drug may be delayed
-drug elimination by metabolism and excretion will be
delayed.
responsible for prolonging the effect of the drug

13. Factors affecting drug distribution…
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 A low plasma protein level may occur in:
-old age
-malnutrition
 Illness such as liver disease, chronic renal failure where
there is excessive excretion of albumin.
 In each case the result is a smaller proportion of drug in
bound form and more free drug in the plasma.
 able to produce a greater therapeutic effect

14. Factors affecting drug distribution (Cont.):
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6. Tissue drug binding (tissue localization of drugs):
 Drugs may bind to intracellular molecules
 The affinity of a tissue for a drug may be due to: binding
to tissue proteins or to nucleic acids, dissolution in the
lipid
e.g. The concentration of chloroquine in the liver is due to the binding
of the drug to DNA.
e.g. Barbiturates distribute extensively into adipose tissue,
b/c of lipid solubility
e.g. Tetracycline bind to bone thus should be avoided in young children
or discoloration of permanent teeth may occur

15. (Cont.):
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 Other distribution considerations
A. Body composition of the very young and the very old may be
quite different from 'normal’
Eg. Total body water( more in infants), Fat content (elder), BBB( infants),
Plasma protein content ( infants and adults)
A. The obese patients –large adipose tissue than body water
• Drugs which are relatively polar has volume of distribution
values may be lower than normal.
• apparent volume of distribution of antipyrine is 0.62l/kg in normal
weight subjects but 0.46l/kg in obese patients
• digoxin and gentamicin are also quite polar

16. Drug metabolism
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Def. The irreversible biotransformation of drug in the body
 Drug metabolism often converts lipophilic chemical
compounds into:
 more hydrophilic, more water soluble
 have their actions decreased (become less effective)
phenytoin to p-hydroxy phenytoin
 increased (become more effective) eg enalapril to
enalaprilat
 Equal activity: eg phenylbutazone to oxyphenbutazone
 May be converted to less toxic or more toxic metabolites

17. Drug metabolism
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18. Drug metabolism…
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 The metabolism of drugs takes place mainly in the liver
(the smooth endoplasmic reticulum of the liver cell).
 However, kidney, lung, intestine and placenta can also
be involved in this process
 Occasionally the metabolite is less water soluble.
 Example is the acetyl metabolite of some of the sulfonamides.
-Precipitated in urine, crystalluria.

19. Drug metabolism
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20. Drug metabolism
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21. Phases of metabolism:
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Phase I reactions:
 Change drugs to more hydrophilic metabolites
-more readily excreted
 Introduce into the drug molecule sites for phase II reactions
 May be less toxic (but not always)
 Mostly occur in the endoplasmic reticulum (microsomes) of
liver cells.
 Usually involve oxidation, reduction, hydrolysis or other
reactions ( Reading assignments)

22. Phase two reactions
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Conjugation
 Conjugation reactions covalently add large, polar
endogenous molecules to parent drug or Phase I
metabolite →inactive and excretable
 (glucuronide, glutathione, sulfate, acetate, amino acids
etc)
 Readly avaliable, can combine easily, in close association with the
microsomal mixed function oxidases

23. Phases of metabolism…
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Glucuronidation
 This is the main conjugation reaction in the body.
-Readily available source of conjugating moiety
-viz. alcohols, acids, amines, etc. can combine easily
-All mammals have the common ability to produce
glucuronides
-The glucuronidation enzymes are in close association with
the microsomal mixed function oxidases
-glucuronidation can take place in most body tissues

24. Phases of metabolism…
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I. Induction
 Induction ~ ↑ metabolic activity of enzyme = ↓ [drug]
E.g. Phenobarbitone will induce the metabolism of itself,
phenytoin, warfarin, etc.
E.g. Cigarette smoking can cause increased elimination of
theophylline.
E.g. alcohol
 Dosing rates may need to be increased to maintain effective
plasma concentrations

25. Phases of metabolism…
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II. Inhibition
 Inhibition ~ ↓ metabolic activity of enzyme = ↑ [drug]
e.g. grape fruit juice
 For example, warfarin inhibits tolbutamide
elimination which can lead to the
accumulation of drug.
 Cimetidine is a therapeutic agent that has been
found to impair the in vivo metabolism of other drugs

26. Diseases and Drug Metabolism:
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Liver Disease:
 Acute or chronic diseases that affect liver function markedly affect
hepatic metabolism of some drugs.
 fat accumulation, alcoholic cirrhosis, biliary cirrhosis, and acute viral
or drug hepatitis.
 may impair hepatic drug-metabolizing enzymes, and thereby
markedly affect drug elimination.
 Eg., The half-life of diazepam inpatients with liver cirrhosis or acute
viral hepatitis is greatly increased, with a corresponding prolongation
of its effect.
Cardiac Disease:
 Cardiac disease, by limiting blood flow to the liver may impair disposition
of those drugs whose metabolism is flow-limited.

27. Excretion
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28. Excretion…
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29. Excretion
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1. Glomerular filtration
2. Active tubular secretion
3. passive tubular reabsorption

30. 1. Glomerular filtration
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 In the glomerulus all molecules (including drugs) of
low molecular weight (less than 2000) are radially
filtered out of the blood unless they are tightly
bounded to plasma protein (Albumin).
 GF and ATS tend to increase the concentration of
drugs in lumen and hence facilitate excretion
whereas tubular reabsorption decreases it and
prevents the movement of drug out of the body.
 The driving force is the hydrostatic pressure, 120 to
130 ml/min is filtered through the glomeruli, the
rate being called as the glomerular filtration rate
(GFR).
 Creatinine, inulin, mannitol and sodium
thiosulphate are used to estimate GFR.

31. 2. Active tubular secretion
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It is a carrier-mediated process which requires
energy against the for transportation of compounds
against concentration gradient.
The system is capacity-limited and saturable.
System for secretion of organic acids/anions like
penicillins, salicylates, glucuronides, sulphates, and
uric acid are secreted.
System for secretion of organic bases/cations like
morphine, mecamylamine, hexamethonium and
endogenous amines such as catecholamines, choline,
histamine, etc.
Drugs undergoing active secretion have
excretion rate values greater than the normal GFR
value.

32. 3. Tubular reabsorption
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 In the distal tubule there is passive
excretion and re-absorption of lipid soluble
drugs.
Filtered lipophilic drugs are extensively
reabsorbed.
Thus if a drug is non-ionized or in the
unionized form it maybe readily reabsorbed.
Many drugs are either weak bases or acids
and therefore the ph of the filtrate can greatly
influence the extent of tubular re absorpation
for many drugs.

33. Drug excretion
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34. Drug Excretion…
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Renal clearance:
 Clearance is defined as the hypothetical volume of body
fluids containing drug from which the drug is removed or
cleared completely in a specific period of time
 quantitatively describing the renal excretion of drugs
 used to investigate the mechanism of drug excretion:
A. if the drug is filtered but not secreted or reabsorbed the
renal clearance will be about 120ml/min in normal subjects.
B. If the renal clearance is less than 120ml/m in then we
can assume that at least two processes are in operation,
glomerular filtration and tubular re-absorption.
C. If the renal clearance is greater than 120ml/m in then
tubular secretion must be contributing to the elimination
process

35. Drug excretion
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36. Renal drug clearance is lower in:
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Elderly and Newborn
Women (20%) than men
Kidney and Heart Disease
Patients taking drugs which block secretion
(aspirin, probenecid)

37. CONT…
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2.Fecal excretion:
 Elimination of toxicants in the feces
 Occurs from two processes:
A-excretion in bile:
 Some heavy metals are excreted in the bile, e.g., arsenic,
lead, and mercury.
 However, the most likely substances to be excreted via
the bile are comparatively large, ionized molecules, such
as large molecular weight (greater than 300) conjugates
e.g. morphine and chloramphenicol, indomethacin (as glucuronide,
glutathione).
 The biliary secretion is active
 There can also be competition between compounds

38. Drug excretion…
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 Since most of the substances excreted in the bile are
water-soluble not likely to be reabsorbed as such.
 However, enzymes in the intestinal flora
hydrolyzing some glucuronide and sulfate
conjugates less-polar compounds that may
then be reabsorbed.
 This process is known as the entero-hepatic
circulation.
prolong the life of the drug in the body

39. Drug excretion…
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 Another way that drugs can be eliminated via the feces is
by:
B-direct intestinal excretion:
 Orally administered drugs may be excreted in the feces if
they are incompletely absorbed or not absorbed at all
(e.g. Cholestyramine)
 Increasing the lipid content of the intestinal tract can
enhance intestinal excretion of some lipophilic
substances.

40. Drug excretion…
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 For this reason, mineral oil is some times added to the
diet to help eliminate toxic substances, which are known
to be excreted directly into the intestinal tract
 Drugs may be excreted by passive diffusion from:
3.Pulmonary excretion:
 The lung is the major organ of excretion for gaseous and
volatile substances.
 Most of the gaseous anesthetics are extensively
eliminated in expired air.

41. 4.Salivary excretion
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 Drug excretion into saliva appears to be dependent on
pH partition and protein binding.
 Basic drugs are excreted more in saliva as compared to
acidic drugs
e.g. caffeine, theophylline, phenytoin, carbamazepine,
etc
 In some instances, salivary secretion is responsible for
localized side effects

42. Drug excretion
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 E.g. Excretion of antibiotics may cause black hairy
tongue,
-Super infection from antibiotics.
-Dental mottling upon tetracycline ingestion.
5.Skin excretion:-
is responsible to some extent for the urticaria and
dermatitis and other hypersensitivity reactions.
Iodine, bromine, benzoic acid, salicylic acid, lead, arsenic
mercury, iron and alcohol are examples of compounds that
excreted in sweat

43. Drug excretion…
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6. Mammary excretion:
 Both a-basic substances and lipid-soluble compounds
can be excreted into milk.
-milk is more acidic than blood plasma.
-milk contains 3-4% lipids,
 lipid-soluble drugs can diffuse along with fats from plasma
into the mammary gland.
 Substances that are chemically similar to calcium can
also be excreted into milk along with calcium
 Ethanol and tetracycline enter the milk by diffusion
through membrane pores( of mammary alveolar cells).
 some potent drugs such as barbiturates, morphine and
ergotamine may induce toxicity in infants

44. Ends & ???
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