This document provides an overview of pharmacokinetic principles related to absorption and distribution of drugs. It defines key terms like pharmacokinetics, bioavailability, and apparent volume of distribution. The factors that determine absorption like pH, blood flow, surface area, and P-glycoprotein expression are described. Distribution is affected by regional blood flow, plasma and tissue protein binding, and lipid solubility. Apparent volume of distribution indicates what volume the drug appears to be distributed in based on plasma concentration.

1. Pharmacokinetics Principles-1
(Absorption & Distribution)
Dr. M. Ahsan, MBBS, MD

2. Learning Outcomes
By the end of the lecture, the students must be able to:
Define Pharmacokinetics
List the different pharmacokinetic properties
Describe the factors determining absorption of drug
Describe bioavailability
Define bioequivalence and therapeutic equivalence
Describe the factors determining distribution of drugs
Describe apparent volume of distribution

3. Introduction
Following administration, the drug must be
absorbed (by crossing membrane barriers)
then distributed (usually via blood vessels and lymphatics)
The drug must survive
metabolism (primarily hepatic)
elimination (by the kidney and liver and in the feces)
The drug molecule has
to cross many
restrictive barriers to
reach its target site

4. Pharmacokinetics
It refers to “what the body does to a drug”
It is the study of drug movement in the body and the alteration of the
drug by the body
Pharmacokinetic properties include ADME:
Absorption
Distribution
Metabolism
Excretion

5. (Absorption)

6. Absorption
• Absorption is the transfer of drug from the site of administration to
the blood stream
• Mechanisms of absorption:
Passive diffusion
Facilitated diffusion
Active transport
Endocytosis and exocytosis

7. Drug movement across membranes

8. Mechanism of Absorption: Passive diffusion
• Drug moves along the concentration gradient
ie. from higher conc. to lower conc.
Movement does not involve carrier
No energy is required
Not saturable
Shows low structural specificity
 Water soluble drugs
penetrate through
aqueous channels or
pores
 Lipid soluble drugs
readily move across
biological
membranes

9. Mechanism of Absorption: Facilitated
diffusion
• Specialized transmembrane carrier proteins facilitate passage of large
molecules
• Carrier proteins undergo conformational change to transport drugs
Drugs move from high conc to low conc
No energy is required
Can be saturated
Inhibited by drugs that compete for the carrier

10. Mechanism of Absorption: Active transport
• Energy-dependent transport involving a specific carrier protein
Drugs can move against the conc gradient
Shows saturation kinetics
Active transport is selective
Can be competitively inhibited by other co-transported substances

11. Mechanism of Absorption: Endocytosis and
exocytosis
• Endocytosis is engulfment of the drug by the cell membrane and
transport in the cell in a drug-filled vesicle
• Exocytosis is reverse of endocytosis
• It is used to transport drugs of large size across membranes
Vitamin B12 is absorbed by endocytosis from the GIT
Neurotransmitters are stored in vesicles and released by exocytosis

12. Factors affecting absorption
• pH
• Blood flow to absorption site
• Total surface area available for absorption
• Contact time at the absorption surface
• Expression of P-glycoprotein

13. Factors affecting absorption
• pH:
A drug crosses biological membrane readily if it is uncharged
(unionized/uncharged drug is lipid-soluble)
• Acidic drugs like aspirin are largely unionized at gastric pH
• Basic drugs are absorbed from the intestine
Weak acids are unionized at acidic pH
Weak bases are unionized at basic pH
pKa of a drug is the pH at which the drug is 50% ionized
(The lower the pKa of a drug the more acidic it is)

14. Factors affecting absorption
• Blood flow to the absorption site:
Intestine has more blood flow than stomach, so more absorption
occurs from intestine
Hot fomentation and exercise increases absorption from
intramuscular site
Shock decreases absorption from subcutaneous route
Greater the blood flow to the absorption site, more is the absorption

15. Factors affecting absorption
• Total surface area:
Microvilli present on intestinal brush-border greatly increase the
surface area , increasing absorption of drug across the intestine
Greater the surface area, more is the absorption

16. Factors affecting absorption
• Contact time at the absorbing surface:
If a drug moves through GIT very quickly (in diarrhoea), it is not well
absorbed
Anything that delays gastric emptying, delays absorption
More is the contact time, more is the absorption

17. Factors affecting absorption
• Expression of P-glycoprotein
In areas of high expression, P-glycoprotein reduces drug absorption
P-gp is a transmembrane transporter that “pumps” drugs “out” of the cell.
It is associated with multidrug resistance.
It is expressed in the liver, kidneys, placenta, intestines, and brain capillaries.

18. Bioavailability
• It is the fraction of administered drug that reaches the systemic
circulation in unchanged form
• It is important for calculating drug doses for non-intravenous routes
If 100 mg of the drug is administered orally and 70 mg reaches the
systemic circulation in unchanged form, the bioavailability is 70%

19. Bioavailability
• It is determined by comparing the plasma levels of a drug after a
particular route of administration with plasma drug levels achieved by
i.v injection
• When a drug is given orally, by plotting the plasma concentration vs
time graph, AUC gives the bioavailability
• Bioavailability of i.v given drug is 100%

20. Bioavailability
• Factors affecting bioavailabilty:
First-pass hepatic metabolism
Solubility of drug
Chemical instability
Nature of drug formulation

21. Bioavailability
• First-pass hepatic metabolism:
When a drug is absorbed across the GIT, it first enters the portal
circulation
If the drug is rapidly metabolised in the liver or gut wall during this
initial passage, the amount of drug that reaches the systemic
circulation in unchanged form is decreased
Eg. 90% of nitroglycerine is cleared during single passage through the
liver, which is why it is given through the sub-lingual route

22. Bioavailability
• Solubility of drug:
• For a drug to be absorbed, it must be soluble in aqueous solutions
• Drugs which are poorly soluble are poorly absorbed and hence have
low bioavailability

23. Bioavailability
• Chemical instability:
• Penicillin G is unstable at gastric pH
• Insulin is destroyed by gastric enzymes
• Thus, their oral bioavailability is very poor

24. Bioavailability
• Nature of drug formulation:
• Factors that influence the ease of dissolution, alter rate of absorption
and hence bioavailability
Particle size
Salt form
Enteric coatings
Presence of excepients

25. Bioequivalence
• Two related drug preparations are bioequivalent if they show
comparable bioavailability and similar times to achieve peak blood
concentrations

26. Drug distribution
• It is the process by which a drug reversibly leaves the bloodstream
and enters the extracellular fluid and tissues.
• It is affected by:
Differences in regional blood flow
Binding of drugs to plasma proteins and tissue proteins
Presence of tissue-specific transporters
Lipid solubility

27. Redistribution: effect of difference in regional
blood flow
Highly lipid soluble drugs
get initially distributed to
organs with high blood
flow (eg. Brain, heart,
kidney etc)
Later less vascular but
more bulky tissues
(muscle, fat) take up the
drug
Plasma drug
concentration falls
Drug is withdrawn from
highly perfused sites
If the site of action was
one of the highly perfused
organs, redistribution
results in termination of
drug action
Eg. Anaesthetic action of
thiopentone sod. injected
i.v is terminated in few
minutes due to
redistribution

28. Capillary permeability
• Capillary endothelial cells in brain have tight junctions and lack large
paracellular spaces.
• Further, a layer of neural tissues covers the capillaries
• Together they constitute the blood-brain barrier (BBB)
• The BBB limits the entry of nonlipid-soluble drugs into the CNS
Inflammation of meninges increases permeability of the BBB

29. Plasma protein binding
• Drugs bound to plasma proteins are:
• Restricted to the vascular compartment..(does not cross biological
membrane)
• Not available for action…(it is in equilibrium with free form)
• Not available for metabolism
• Not available for excretion by kidneys
• One drug can displace other drug from protein-binding sites
Highly protein-bound drugs
are long acting
Acidic drugs bind to plasma
albumin and basic drugs bind to
α1 acid glycoprotein

30. Tissue protein binding
• Drugs may accumulate in specific organs by active transport or get
bound to specific tissue constituents
• Tissue reservoirs act as major source of drug and prolong its action or
cause local drug toxicity

31. Apparent volume of distribution (Vd)
The volume that would accommodate all the drug in the body if the
concentration throughout was the same as in plasma
Once a drug enters the body, into any one of the three compartments:
1. Plasma compartment
2. Extracellular fluid
3. Total body water

32. Apparent volume of distribution
Vd depends on :
Lipid solubility
Plasma protein binding
Tissue sequestration
pKa of the drug
Age, sex, obesity, pregnancy
Diseases like CHF, uremia, cirrhosis
Drugs with high vol. of
distribution are not easily
removed by dialysis in case of
poisoning

33. Determination of Vd
Vd = dose administered i.v
plasma concentration
If 10mg of drug is injected in a patient and the plasma concentration is
1 mg/L, then Vd is 10 L

34. Effect of Vd on drug half-life
If a drug has a large Vd, most of the drug is in the extraplasmic space
and is unavailable to the excretory organs
Thus, drug half-life will be high
[An extremely high Vd indicates that the drug is sequestered in some
tissue]

35. References
• Lippincott Illustrated Reviews: Pharmacology(6th ed.). Philadelphia,
PA: Wolters Kluwer.