This document discusses various concepts related to drug distribution in the body after administration. It explains that drugs may be distributed to tissues like blood, interstitial fluid, intracellular compartments, body fat, bones, placenta, brain, liver and more. It provides details on body fluid volumes and total body water. The concept of volume of distribution is introduced, which is the apparent volume required to account for the total amount of drug in the body based on the plasma concentration. Factors affecting drug distribution like lipid solubility, ionization, plasma protein binding, regional blood flow and tissue transporters are also summarized.

1. Distribution
Dr. Chintan Doshi

2. Drug
administration
Entry in blood
stream
Distributed to
tissues

3. DRUG ADMINISTRATION
May get distributed
to…..
Vascular compartment (blood)
Interstitial fluid compartment (ISF)
Intracellular compartments (ICF)
Body fat
Bones
Placenta
Brain
Plasma proteins
Liver
Many more organs !!!

4. Body fluid
Blood (plasma) – 5% of body weight
Interstitial fluid – 15% of body weight
Intracellular fluid - 40% of body weight
ECF
20%
TBF
60%
In 70 kg individual L per kg
BLOOD = 70*5/100 = 3.5 L 0.05 L/kg
ISF = 70*15/100 = 10.5 L 0.15 L/kg
ICF = 70*40/100 = 28 L 0.4 L/kg
TBF = 70*60/100 = 42 L 0.85 L/kg

5. • Keep your imagination on fire.
• Try to imagine the hypothesis.

6. Volume of distribution (Vd)
• Apparent Vd
• “The volume that would accommodate all the
drug in the body, if the concentration
throughout was same as in plasma.”

7. 70 kg
42 L
420 mg
Vd= 42 L
Concentration = 420 mg/42 L
Concentration same as in plasma
Plasma concentration =amount / Vd
Vd = amount/ plasma concentration

8. Vd(L) =
Total amount administered
Plasma concentration
It is express in L/kg

9. Figures showing aVd
Vd =
plasma
0.05 L/kg
Vd =
ECF volume
0.2 L/kg
Vd = total body
water
0.8 L/kg
Vd > total body
water

10. • This example is PURELY HYPOTHETICAL.
• It denotes the over all pattern of distribution.
• It doesn’t denote the ANATOMICAL mode of
drug distribution.

11. Vd(L) =
Total amount administered
Plasma concentration
Total amount administered
Plasma concentration
Vd(L) =
When plasma
concentration
is high….
Vd is low….
Vd(L) =
Total amount administered
Plasma concentration
When plasma
concentration
is low….
Vd is high….

12. • So if a drug remains in vascular compartment 
lower Vd.
• If a drug gets concentrated in peripheral tissues like
heart, retina, liver,  higher Vd.

13. Factors
affecting
distribution
Lipid
solubility
Ionization
Binding to
plasma &
tissue
protein
Presence of
tissue
specific
transporters
Differences
in regional
blood flow.

14. Redistribution
• For highly lipid soluble drugs
• Redistribution α lipid solubility
• Eg thiopentone

15. BBB

16. Penetration into brain and CSF
• ANATOMICAL BARRIERS :
– BBB
• Only lipid soluble, carrier mediated transport
• Dopamine vs Levodopa
• In case of inflammatory diseases
– BCB
• FUNCTIONAL BARRIERS :
– Efflux transporters
– like p-glycoprotein and OATP
– Enzymatic mechanisms
– like MAO, cholinesterase

17. PLASMA PROTEIN BINDING
• Most drugs possess affinity for plasma
protiens
• Acidic drugs bind to Albumin
– Acidic drugs are …salicylates, valproic acids, phenytoin, sulfonamide,
warfarin.
• Basic drugs bind to α-1-acid glycoprotein.
– Basic drugs are : quinidine, propranolol,lignocaine, verapmil,
methadone.
• Express in term of %
• Eg diazepam 99%

18. • While we measure concentrateon  it
involves both (FREE +BOUND)
• But action is performed by free fraction only…
so can such estimations can be misleading.

19. PLASMA PROTEIN BINDING :
• Absorption PP bound drugs can not be absorbed
• Distribution can not cross membrane
• Metabolism can not be metabolized
• Excretion  can not be excreted
• Action  can not act, only free form is active.
• Duration of action  usually have longer duration of action.

20. PLASMA PROTEIN BINDING
Clinical significance
1. Highly plasma protein bound drug – Vd ? Less or more?
Vd is less
2. Bound form is not available for action
3. High PP binding makes drug long acting, (temporary storage)

21. PLASMA PROTEIN BINDING
Clinical significance
4. Displacement interaction.
• “Competition occurs when they bind
the same site”
– Sulfonamide displace warfarin
• No competition when they bind to
different site on same PP
– Eg probenecid and indomethacin

22. PLASMA PROTEIN BINDING
Clinical significance
5. Disease
• Hypoalbuminemia - ↓ albumin
• Pregnancy, inflammation, MI - ↑ glycoprotien
Diseases causing
lowering of
plasma proteins
Less binding of
drug
Increase in
concentration of
“FREE” drug
Pronounced effect/
toxicity

23. Dialysis in Drug Poisoning
• Dialysis does not filter proteins.
• Drugs having high plasma protein binding
(e.g. diazepam) cannot be removed by dialysis
• Drugs having high volume of
distribution:Diffucult to remove by dialysis
Digoxin

24. Contd.
• Drugs having low Vd are easily removed by
dialysis
Aspirin

25. •THANK YOU

26. • Cytochrome P450 most commonly involved
in drug metabolism
• (a) CYP 3A4
• (b) CYP 1AI
• (c) CYP 2E1
• (d) CYP 2D6

27. • Which of the following is a Phase I metabolic
reaction?
• (a) Hydroxylation
• (b) Conjugation
• (c) Glucuronidation
• (d) Sulfation

28. • In drug metabolism, hepatic cytochrome P-450
system is responsible for: (Karnataka 2003)
• (a) Phase I reactions (hydrolysis, oxidation, reduction
etc.) only
• (b) Phase II reactions (conjugation, synthesis etc.) only
• (c) Both phase I and II reactions
• (d) Converting hydrophilic metabolites to lipophilic
metabolites

29. • One of the potent microsomal enzyme
inducer drug is:
• (a) Captopril
• (b) Erythromycin
• (c) Rifampicin
• (d) Cimetidine

30. • Apparent volume of distribution (aVd) is
more than total body fluid if drug is:
• (a) Poorly soluble
• (b) Sequestered in tissues
• (c) Slow elimination
• (d) Poorly plasma protein bound

31. • Which of the following can result in oral
contraceptive failure?
• (a) Valproate
• (b) Rifampicin
• (c) NSAIDs
• (d) Ethambutol

32. • SLE like reaction is caused by:
• (a) Hydralazine
• (b) Rifampicin
• (c) Paracetamol
• (d) Furosemide

33. • The bioavailability of the drug depends upon:
• (a) First pass metabolism
• (b) Second pass metabolism
• (c) Volume of distribution
• (d) Excretion