Biopharmaceutics

1. DRUG DISTRIBUTION
Prepared By
Girijesh Kumar Pandey
M.Pharm. (Pharmaceutics)

2. Contents
• Distribution of drugs: Introduction
• Tissue permeability of drugs,
• Special compartments for drug distributions
• Plasma protein binding of drugs,
• Kinetics of protein binding,
• Factors affecting protein-drug binding.
• Significance of Protein-Drug binding
• Apparent volume of drug distribution,
• Clinical significance of protein binding of drugs
• Redistribution of drugs

3. Distribution of drugs:
Introduction
• Distribution of drugs
• Movement of drug from blood into tissue
– a) 1 st distributed to liver, kidney, brain
– b) 2nd distribution phase( min to hrs )- muscle,
skin, fat
• Reversible transfer of drugs between one
compartment and another (between blood &
extravascular fluids & tissues)

4. Distribution of drugs:
Introduction

5. Distribution of drugs:
Introduction
• Distribution is predominantly a passive
process - The driving force is the
concentration gradient between the blood
and extravascular tissues
• Process occurs by the diffusion of free drug
until equilibrium is established

6. Tissue permeability of drugs
• As the pharmacological action of a drug
depends upon its concentration at the site of
action distribution plays a significant role in
the onset, intensity, and duration of action.
• Distribution of a drug is not uniform
throughout the body because different tissues
receive the drug from plasma at different rates
and to different extents.

7. Tissue permeability of drugs

8. Tissue permeability of drugs
• Blood brain barrier
– Constraints passage of drug to brain and CSF
– Number efflux transporters at BBB(Molecular barrier)
– Clinical importance - Protects brain tissue
• 1. Toxic substances in blood
• 2. Peripheral neurotransmitters
– Only lipid soluble non ionised drugs penetrate easily to
brain
• e.g. volatile anaesthetics, ultra short acting barbiturates, narcotic
analgesic, dopamine precursors and sympathomimetics
– Water soluble ionised drug fail to penitrate BBB
• • e.g. dopamine ,serotonine , streptomycin, quaternary substances

9. Tissue permeability of drugs
• Placental barrier
– Lipid in nature Allow transfer of non polar lipid soluble
substances by passive diffusion
– Other mechanisms
• 1. Active transport e.g. amino acid and glucose
• 2. Pinocytosis e.g. maternal immunoglobin
– Some degree of foetal exposure likely to occur
virtiualy in all drugs
– Teratogenic drug - first trimester
• Thalidomide Phenytoin Trimethadione streptomycin
Methotrexate

10. Tissue permeability of drugs
• Drug administer in last trimester affect vital
function of fetus
• Morphine - Fetal asphyxia
• Antithyroid drugs - Neonatal goitre
• Hypoxia increase placental permeability for
drugs

11. Tissue permeability of drugs
• Blood testis barrier
• Located at the sertoli -sertoli cell junction
• Tight junction between neighboring sertoli
cells that act as barrier
• Restrict the passage of drugs to spermatocyte
and spermatids

12. Special compartments for drug
distributions
• Cellular reservoir
– Drugs that have high affinity to tissue proteins
– 1. Digoxin , emetine – skeletal muscle , heart , liver , kidney
– 2. Iodine – thyroid
– 3. Chloroquine- liver , retina
– 4. Cadmium , lead , mercury – kidney
• Fat as reservoir
– Highly lipid soluble drugs ( DDT and thiopentone )
accumulate in adipose tissue
– Starvation
– Drug toxicity

13. Special compartments for drug
distributions
• Transcellular reservoir
– Aqueous humour – Chloramphenicol , prednisolone
– CSFAminosugars and sucrose
– Joint fluid – Ampicillin
– Pleural fluid – Imipramine and methadone
– Bones & connective tissue
– Tetracyclines , cysplatin , lead , arsenic , flourides –
Form complex with bones
• Antifungal drugs accumulates in skin and finger
nails

14. Plasma protein binding of drugs
• Plasma protein binding as drug reservoir
• Drugs bind to plasma proteins or cellular
proteins in reversible and dynamic equilibrium
Protein bound drug not accessible
• Capillary diffusion Metabolism Excretion
• Important proteins that contribute to drug
binding

15. Plasma protein binding of drugs
• Plasma albumin (acidic drugs) 1.Warfarin
2.Penicillin 3.Sulfonamides 4.Tolbutamide
5.Salycylic acid
• Alpha 1 acid glycoprotien Acute phase reactant
(basic drugs) 1.Quinidine 2. Imipramine 3.
Lidocaine 4. Chlorpromazine 5. Propranalol
• Drugs bound to tissue proteins and
nucleoproteins (High aVd) Example 1.Digoxin
2.Emetine 3.Chloroquine

16. Plasma protein binding of drugs
• Miscellanous protein binding
• 1.Corticosteroid - Transcortin globulin
2.ThyroxineAlpha globulin
• Clinically important aspects of plasma protein
binding
• 1. High plasma protein bound drug- Vd lower
• 2. High protein bound
• Difficult to remove by dialysis
• 3. Binding of drugs to plasma proteins capacity
limited and saturable

17. Kinetics of Protein binding
Consider, if “P” represents protein and “D” the drug then
applying law of mass action to reversible protein-binding
binding
P + D  PD
At equilibrium,
Ka = [PD] / [P] [D]
[PD] = Ka [P] [D]
Where,
[P] – concentration of free protein
[D] – concentration of free drug
[PD] – concentration of free - drug complex
Ka – association rate constant

18. Kinetics of Protein binding
If “P T ” is the total concentration of protein present, unbound
and bound, then :
P T = [ PD ] + [P]
If “ r” is the number of moles of drug bound to total moles of
protein,
then , r = [ PD ] / PT
= [ PD ] / [ PD ] + [P]
r = Ka [P] [D] / Ka [P] [D] + [P]
= Ka [D] / Ka [D] + 1
The above equation holds when there is only one binding site
on the protein and the protein – drug complex is a 1:1
complex

19. Kinetics of Protein binding
If more than one or N number of binding sites are available
per molecule of protein then :
r = N Ka [D] / Ka [D] + 1
The value of association constant,
Ka and the number of binding sites N can be obtained by
plotting the above equation in four different ways:
• Direct plot
• Scatchard plot
• Klotz plot
• Hitchcock plot

20. Kinetics of Protein binding
1) Direct Plot Method :
- A direct plot of “r” Vs *D+ can be used to find out the no of
binding sites on protein ‘n’ (plateau value).
- Ka is obtained by finding drug conc. required to saturate the
half of the total binding sites available ( i.e ; n/2).

21. Kinetics of Protein binding
2) Scatchard Plot:
Obtained by rearranging an equation into linear form.
r = nK a [D] / K a [D] + 1
r + rK a [D] = nK a [D]
r = nK a [D] – rK a [D]
r = nK a – rK a [D]
A plot of r/[D] Vs r yields a st.line with X & Y intercepts
equal to ‘n’ & ‘ nKa ’ & the slope is equal to Ka.

22. Kinetics of Protein binding
Scatchard Plot:

23. Kinetics of Protein binding
3) Double Reciprocal Plot Or Klotz Plot: ( Line
Weaver -Burk Plot )
Reciprocal of equation gives-
1/r= 1/ nka (D)+1/n
A plot of 1/r Vs 1/D yields a double reciprocal
plot.
It is straight line with slope 1/ Nka and Y-
intercept 1/N.

24. Kinetics of Protein binding
• Double Reciprocal Plot Or Klotz Plot:

25. Kinetics of Protein binding
4) Hitchcock Plot
• It is made by rearranging the equation as –
N Ka [D] / r = 1 +Ka
• dividing both sides by Nka gives –
[D] / r = 1/ NKa + [D]/N
• A plot of [D] / r Vs [D] yields a straight line
with slope 1/N and intercept 1/ NKa

26. Kinetics of Protein binding
• Hitchcock Plot

27. Factors affecting protein-drug
binding
1. Drug - related factors
• a) Physicochemical characteristics of the drugs b)
Concentration of drugs in the body
• c) Affinity of drug for a particular binding components
2. Protein / Tissue related factors
• a) Physicochemical characteristics of the protein or
binding agents
• b) Concentration of protein or binding components
• c) Number of binding sites on the binding agents

28. Factors affecting protein-drug
binding
3. Drug interactions
• a) Competition between drugs for the binding site
• b) Competition between the drug and normal body
constituents
• c) Allosteric changes in protein molecule
4. Patient-related factors
• a) Age
• b) Intersubject variations
• c) Disease states

29. Significance of Protein-Drug
binding
1. Absorption
– The absorption equilibrim is attained by transfer
of free drug from the site of administration to the
systemic circulation. Following the equilibrium the
process may stop.

30. Significance of Protein-Drug
binding
2. Distribution
– A protein bound drug in particular does not cross the
BBB, the placental barrier, the glomerulus.
– Thus protein binding decreases the distribution of
drugs.
3. Metabolism
- Protein binding decreases the metabolism of drugs &
enhances the biological half life.
- Only unbound fraction get metabolized.
- e.g. Phenylbutazone & Sulfonamide

31. Significance of Protein-Drug
binding
4. Elimination
-Only the unbound drug is capable of being eliminated. -
Protein binding prevent the entry of drug to the
metabolizing organ (liver ) & to glomerulus filtration.
e.g. Tetracycline is eliminated mainly by glomerular
filtration.
5. Systemic solubility of drug
-Lipoprotein act as vehicle for hydrophobic drugs like
steroids, heparin, oil soluble vit.
6. Drug action
Protein binding inactivates the drugs so sufficient
concentration of drug can not be build up in the receptor
site for action. • e.g. Naphthoquinone

32. Significance of Protein-Drug
binding
7. Sustain release
– The complex of drug protein in the blood act as a
reservoir & continuously supply the free drug.
– e.g. Suramin sodium-protein binding for
antitrypanosomal action.
8. Diagnosis
– The chlorine atom of chloroquine replaced with
radiolabeled I131 can be used to visualize-
melanomas of eye & disorders of thyroid gland.

33. Apparent volume of
distribution
• Total space which should be available in body to
contain known amount of drug
aVd = total amount of drug(mg/kg) /
Concentration of drug in plasma (mg/l)
• aVd of some drugs is much more than actual body
volume
• Widely distributed in body
• Digoxin, imipramine, phenobarbitone & analogues of
morphine
• Difficult to remove by dialysis if toxicity occurs
• Drugs good candidates for dialysis – drugs with low Vd
& low plasma protien bound

34. Clinical significance of large
volume of distribution
• May require a loading dose initially for quick onset of action
– E.g. chloroquine used in malaria Tb Chloroquine 600mg stat as
loading dose followed by 300mg after 8hrs & then 300mg daily for
next 2days
• aVd < 5L –
– Drug is retained in vascular compartment
• e.g. Heparin ,insulin ,warfarin & furosemide
• aVd≈15L –
• Drug is restricted to extracellular fluid • e.g.aspirin,tolbutamide
,gentamicin
• aVd>20L
• Drug is distributed through total body water (e.g. Ethanol,
phenytoin methyl dopa & theophylline) or • Penetration in various
tissues (e.g. Digoxin ,imipramine ,morphine,chloroquine)

35. Redistribution of drugs
• Redistribution of drugs
• Highly lipophilic drugs – distribute to brain,
heart kidney etc., that will be immediately
followed by muscle and fats.
• Distribution is transfer of drug from blood into
tissues
• Factors affecting it are sanctuary reservoirs of
drugs and redistribution phenomenon.

36. Redistribution of drugs
• Redistribution

37. References
• Biopharmaceutics and Pharmacokinetics - A treatise 2nd Edition by
D. M. Brahmankar and Sunil B. Jaiswal, Vallabh Prakashan, New
Delhi.
• http://www.columbia.edu/itc/gsas/g9600/2004/GrazianoReadings/
Drugabs.pdf
• https://www.slideshare.net/virajshinde9659/absorption-and-
distribution-of-drugs-83455166
• Goodman and gillman 12th edition The pharmacological basis of
therapeutics
• https://www.slideshare.net/bharathpharmacist/factors-affecting-
protein-drug-binding-and-its-kinetics-39685908
• https://www.slideshare.net/SnehalPatel98/protein-drug-binding-
84925362
• http://www.authorstream.com/Presentation/nagasiva945-
1601393-kinetics-protein-binding/