biotransport, absorption, distribution

2. CLINICAL PHARMACOKINETICS
LEARNING OBJECTIVES
I. Processes involved in pharmacokinetics of
drugs
II. Mechanisms of drug passage across cell
membranes
III. Bioavailability and factors affecting it

3. CLINICAL PHARMACOKINETICS
IV. Implications of protein binding of drugs
V. Processes of biotransformation and factors
affecting it
VI. Routes of drug excretion and half-life

4. I. Processes involved in
Pharmacokinetics of drugs
A. ABSORPTION OF DRUGS
B. DISTRIBUTION OF DRUGS
C. BIOTRANSFORMATION(METABOLISM) OF
DRUGS
D. EXCRETION OF DRUGS

5. MECHANISMS OF DRUG ABSORPTION
A. Transcellular/intracellular transport
B. Paracellular/intercellular transport
C. Vesicular transport
A. Transcellular/Intracellular Transport
passage of drugs across the GI epithelium.
most common pathway for drug transport.
3 steps involved
(i) Permeation through GI epithelial cell membrane, a
lipoidal barrier
(ii) Movement across the intracellular space (cytosol).
(iii) Permeation through lateral or basolateral
membrane

8. Transcellular transport – two types, passive and
active
1. Passive Transport Processes
do not require energy to pass through the
lipid bilayer.
further classified as
a. Passive diffusion.
b. Pore transport.
c. Ion-pair transport.
d. Facilitated diffusion.

9. 2. Active Transport Processes
Requires energy from ATP to move drug
molecules
Two types
a. Primary active transport.
b. Secondary active transport – subdivided into
two
i. Symport (co-transport).
ii. Antiport (counter-transport).

11. A. ABSORPTION OF DRUGS
• Mechanisms of drug passage across cell
membranes (9)
• Bioavailability: Factors affecting bioavailability
- I (a-e)
- II (a-f)
- III (a-i)
- IV ( a[i-iii] ), b[i-ii]
- V (a[i-iii], b, c, d
31 approximately

12. A. ABSORPTION OF DRUGS
• Mechanisms of drug passage across cell
membranes (9)
1. Convection (solvent drag)
2. Simple(passive)diffusion
3. Channel mediated diffusion(diffusion
through aqueous pores or pore transport)
4. Carrier mediated (facilitated)diffusion
[uniport]

13. A. ABSORPTION OF DRUGS
5. ATP-mediated transport (primary active
transport)
6. Ion-pair transport
7. Symport(Co-transport)
8. Antiport ( counter transport )
9. Pinocytosis ( Corpuscular or vesicular or
particulate transport )

14. 1. Convection (solvent drag)
• Dissolved solutes
• Dragged by
• Bulk water flow as seen in renal epithelium and
blood flow as in blood vessels and GIT
• It generally occurs in the paracellular, rather
than transcellular, pathway between the tubular
cells. t is seen e.g. in the passive transport
in renal sodium reabsorption, renal chloride
reabsorption as well as renal urea handling.

15. 2. Passive diffusion
• Most common mechanism
• No energy required
• Moves across the concentration gradient from
higher concentration till equilibrium of free
drug concentration
• Dissolves in aqueous as well as the lipid
medium of the cell membrane
• Lipid soluble drugs diffuse rapidly

16. 3. Diffusion through aqueous pores
( pore transport)
• Particles less than 100 daltons size traverse
through these pores (channels) on cell
membranes
• Seen in kidneys and jejunum

18. 4. Carrier mediated or facilitated
diffusion
• Energy not required
• Transporter (carrier) protein required
• Solute binds to carrier protein and transferred
down the concentration gradient
• Seen in GIT, Biliary tract, BBB and renal
tubules
• Examples B12, Iron, Calcium

20. 5. Ion-pair transport
• A drug with a charge binds with a carrier
protein of opposite charge and this neutral
complex is then transported by passive
diffusion
• Examples quinine, propranolol

22. 6.ATP mediated (primary
active)transport
• Against concentration gradient
• ATP hydrolysed to ADP releasing energy
needed for active transport
• Natural substrate like drugs are transported
thus
• Renal tubular secretion of weak acids and
weak bases also are transported like this
• Examples methyl dopa, l-dopa, 5-FU,
methotrexate

23. 7. Symport or co-transport
• Transport of one solute with another solute in
the same direction uphill
• Seen in kidneys, GIT
• Eg sodium glucose cotransporter-1 & 2

24. 8. Antiport or counter transport
• One solute transported with another solute in
opposite direction with one uphill and another
downhill

26. 9. Pinocytosis (corpuscular, vesicular
or particulate transport)
• Non aqueous liquid droplets or solid particles
are engulfed by processes formed by epithelial
cells. A vesicle or vacuole is formed.
• Examples. Fatty acids, fats, amino acids,
vitamins ADKE. Not significant for drugs.

27. •Endocytosis: large molecular particle
(P) binds to a binding protein (B) on the
surface of the cell.
•Membrane invaginates to form a vesicle
which nicks off, and the vesicle may
remain stored within the cell, or it may
disintegrate to release the substance in
the cytoplasm, or be extruded across the
cell by exocytosis.
•Exocytosis: The particle or the
transmitter/hormone(T/H) stored within
intracellular vesicles, generally as a
complex with a storage protein (S), is
secreted by exocytosis. On activation,
the vesicle translocates to and fuses with
the membrane. All contents of the vesicle
are then poured out in the extracellular
space.

29. Bioavailability
Is the fraction of the administered drug reaching
the systemic circulation in unchanged form
For example
100 mg of a drug is administered
70% of it reaches systemic circulation
unchanged, then bioavailability is expressed
as F=0.7

30. Factors affecting bioavailability of
drugs
I. Physical properties of drugs
II. Formulation characteristics
III. Patient characteristics
IV. Presence of other substances in GIT
V. Pharmacokinetic characteristics of drugs

31. 1. Physical Properties of the drug
a. Physical state of the drug: Gases absorbed
faster than liquids
b. Lipophilic drugs better absorbed
c. Unionised better absorbed than ionised
d. pH: acidic drugs better absorbed in acidic
medium, basic drugs alkaline medium
e. Vehicle used in formulation: aqueous
solution better absorbed than oily solution

32. II. Formulation characteristics
a. Particle size: smaller the particle size, more
surface area, better absorption
b. Amorphous form dissolves faster than
crystalline form
c. Weak organic acids or bases have poor
solubility in water. Their salts have better
solubility and absorption.
acids – phenytoin sodium/potassium
bases- tetracycline HCL/sulphate/phosphate

33. II. Formulation characteristics
d. Adjuncts in formulation
- Magnesium stearate. Coats drug particles,
retard dissolution and absorption
e. Tablet hardness: disintegration and
dissolution rate. Harder, slower. Less
hard(soft) breaks into powder!

34. II. Formulation characteristics
f. Tablet coating
Coating may cause variable dissolution and
absorption profile

35. III. Patient Characteristics
a. Gastric lumen- acidic – favours absorption of
acidic drugs and small intestine- basic- favours
absorption of basic drugs
b. Gastric emptying rate modulates absorption
c. Increased intestinal motility – reduce
absorption
d. Area of absorption: GIT, pulmonary alveolar
epithelium, large area, rapid absorption

36. III. Patient Characteristics
e. Celiac disease, malabsorption syndrome,
hepatic dysfunction etc can reduce absorption
f. Mesenteric blood flow: heavy carbohydrate
meal and hypovolemic states reduce
mesenteric blood flow and absorption rate
g. Circulation to site of absorption:
vasoconstrictors reduce flow and absorption.
Heat, massage increases flow and absorption
rate

37. III. Patient Characteristics
h. Enterohepatic circulation: estradiol
absorption affected
i: surgery- gastrectomy reduces absorption of
some drugs- iron, folic acid, ethambutol,
ethionamide

38. IV. Presence of other substances in
GIT
a. Interaction with other drugs, ions
i. Metoclopramide increases gastric emptying,
atropine reduces
ii. Cholesteramine decreases absorption of
digoxin, PAS decreases rifampicin, vit C
increases iron absorption
iii. Alteration of bowel flora by antibiotics can
decrease absorption

39. IV. Presence of other substances in
GIT
b. Presence of food:
i. Food modulates absorption of drugs
ii. Types of food: calcium rich food reduces
tetracycline. Fatty food increases
albendazole, mebendazole

40. V. Pharmacokinetic characteristics of
drugs
a. Drugs like isoprenaline metabolised in the gut
wall
b. Drug metabolism by bacteria:
i. Penicillinase producing organisms break
benzyl penicillin
ii. Sulfasalizine, olsalizine modified by gut flora
to active sulfide moiety
iii. L-dopa, morphine metabolised by gut flora
partially or wholly

41. Bioavailability
• Bioavailability refers to the rate and extent
of absorption of a drug from a dosage form
administered by any route, as determined by
its concentration-time curve in blood or by its
excretion in urine.
• It is a measure of the fraction (F) of
administered dose of a drug that reaches the
systemic circulation in the unchanged form.
• Bioavailability of drug injected i.v. Is 100%, but
is frequently lower after oral ingestion.

42. Bioequivalence
• Two products are considered to be
bioequivalent when they are equal in the rate
and extent to which the active pharmaceutical
ingredient (API) becomes available at the
site(s) of drug action
• Its significance; a brand is substituted with
another brand ( availability issue ) or generic
product ( economical )
• Bioavailability (F) and bioequivalence (BE)
studies are mandatory for generic products
and should match with innovator/reference
product.

44. Drug concentration vs time graph

46. Filtration
• Filtration is passage of drugs through aqueous
pores in the membrane or through
paracellular spaces. (pore transfer, bulk flow)
• Seen across most capillaries including
glomeruli.
• Lipid-insoluble drugs cross biological
membranes by filtration if their molecular size
is smaller than the diameter of the pores.

47. Filtration
• Majority of cells (intestinal mucosa, RBC, etc.)
have very small pores (4 A) and drugs with MW
> 100 or 200 daltons are not able to penetrate.
• However, capillaries (except those in brain)
have large paracellular spaces (40 A) and most
drugs (even albumin) can filter through these
• As such, diffusion of drugs across capillaries is
dependent on rate of blood flow through them
rather than on lipid solubility of the drug or pH
of the medium.(oral vs IM absorption)

48. Distribution

49. Steps in drug distribution
Distribution is reversible transfer of a drug between
the blood and the extravascular fluids and tissues. It
Involves:
1. Permeation of free (unbound) drug present in the
blood through the capillary wall (occurs rapidly) and
entry into the interstitial/extracellular fluid (ECF).
2. Permeation of drug present in the ECF through the
membrane of tissue cells and into the intracellular
fluid. This step is rate-limiting and depends upon
two major factors –
(a) Rate of perfusion to the tissue
(b) Membrane permeability of the drug.

52. • blood and the ECF pH normally remain
constant at 7.4, they do not have much of an
influence on drug diffusion unless altered in
conditions such as systemic acidosis or
alkalosis.
• Most drugs are either weak acids or weak
bases and their degree of ionisation at plasma
or ECF pH depends upon their pKa.
• drugs that ionise at plasma pH (i.e. polar,
hydrophilic drugs), cannot penetrate the
lipoidal cell membrane and tissue
permeability is the rate-limiting step in the
distribution of such drugs.

53. unionised drugs which
are generally
lipophilic, rapidly cross
the cell membrane.
thiopental, a nonpolar,
lipophilic drug, largely
unionised at plasma
pH, readily diffuses
into the brain
penicillins which are
polar, water-soluble
and ionised at plasma
pH do not cross the
blood-brain barrier

54. • acidosis (metabolic or respiratory) results in
decreased ionisation of acidic drugs and thus
increased intracellular drug concentration and
pharmacological action.
• Sodium bicarbonate induced alkalosis is useful
in the treatment of barbiturate (and other
acidic drugs) poisoning to drive the drug out
and prevent further entry into the CNS and
promote their urinary excretion by favouring
ionisation.
• Converse is true for basic drugs; acidosis
favours extracellular whereas alkalosis,
intracellular distribution.

55. Physiological Barriers to Distribution of Drugs
Blood-Brain Barrier (BBB):
brain capillaries consist of endothelial cells which are
joined to one another by continuous tight
intercellular junctions comprising what is called
as the blood-brain barrier
pericytes and astrocytes, form a solid envelope
around the brain capillaries. As a result, the
intercellular (paracellular) passage is blocked and
for a drug to gain access from the capillary
circulation into the brain, it has to pass through
the cells (transcellular) rather than between
them.
Sedating vs non sedating antihistamines
Diazepam vs magnesium sulfate

56. Some sites in the brain lack BBB (CTZ and the
median hypothalamic eminence)
Metoclopramide vs domperidone
Drugs administered intranasally may diffuse
directly into the CNS because of the continuity
between submucosal areas of the nose and
the subarachnoid space of the olfactory lobe.
Intranasal spray sumatriptan
Ondansetron nasal spray
There is also absence of pinocytosis in brain

57. • A solute may thus gain access to brain via only
one of two pathways:
1. Passive diffusion
2. Active transport of essential nutrients such as
sugars and amino acids. Thus, structurally similar
foreign molecules can also penetrate the BBB by
the same mechanism.
levodopa, can penetrate the CNS where it is
metabolised to dopamine, is used in its
treatment. Dopamine cannot cross BBB
(treatment of parkinsonism)

58. Blood-Placental Barrier
• maternal and the foetal blood vessels are separated
by a number of tissue layers made of foetal
trophoblast basement membrane and the
endothelium which together constitute the
placental barrier.
• Many drugs having moderate to high lipid solubility
cross the barrier by simple diffusion quite rapidly
• Placental barrier is not as effective a barrier as BBB.
• Nutrients essential for the foetal growth are
transported by carrier-mediated processes.
• Immunoglobulins are transported by endocytosis

59. An agent that causes toxic effects on foetus is called as
teratogen. Teratogenecity is defined as foetal abnormalities
caused by administration of drugs during pregnancy. Drugs
can affect the foetus at 3 stages It is better to restrict all
drugs during pregnancy because of fear of teratogenic
effects.

60. Volume of Different Organs, Blood Flow and Total
Body Volume to be 70 litres

61. • Rapid termination of action of thiopental due to such
a tissue redistribution.
Disease States
a. Altered albumin and other drug-binding protein
concentration.
b. Altered or reduced perfusion to organs or tissues.
c. Altered tissue pH.
In meningitis and encephalitis, the BBB becomes more
permeable and thus polar antibiotics such as
penicillin G and ampicillin which do not normally
cross it, gain access to the brain.
In a patient suffering from CCF, the perfusion rate to
the entire body decreases affecting distribution of all
drugs

62. • VOLUME OF DISTRIBUTION
Volume of plasma required to contain a dose of the drug at
the concentration measured in plasma (blood, serum)
Vd = D/Cp
Volume of distribution = dose/concentration (p)
• Eg
Chloroquine
500 (mg)/ 125(ng/ml)
Convert concentration per liter
125 ng x 1000 ml
1000 ng = 1 mcg
125mcg/L
Convert dose from mg to mcg ; 1mg = 1000 mcg
500 x 1000 mcg
500 x 1000 / 125 = 4000 Lts
Apparent = imaginary (not real) (hypothetical)

63. • The plasma volume can be determined by use of
substances of high molecular weight or
substances that are totally bound to plasma
albumin. When given i.v., these remain confined
to the plasma.
• The total blood volume can also be determined
if the haematocrit is known.
• The extracellular fluid (ECF) volume can be
determined by substances that easily penetrates
the capillary membrane and rapidly distribute
throughout the ECF but do not cross the cell
membranes

64. The total body water (TBW) volume can be
determined by use of substances that distribute
equally in all water compartments of the body
(both intra- and extracellular)
The intracellular fluid volume is determined as the
difference between the TBW and ECF volume.

65. Actual volume of body fluids

67. • Certain generalizations can be made
regarding the apparent volume of
distribution of drugs:
1. Drugs which bind selectively to plasma
proteins or other blood components, e.g.
warfarin has a Vd of about 10 litres.
2. Drugs which bind selectively to extravascular
tissues, e.g. Chloroquine has Vd 15000 Lts.
Such drugs leave the body slowly and are
generally more toxic than drugs that do not
distribute deeply into body tissues.

68. • Apparent volume of distribution is expressed
in litres and sometimes in litres/Kg body
weight. The Vd of various drugs ranges from as
low as 3 litres (plasma volume) to as high as
40,000 litres (much above the total body size).
Many drugs have Vd greater than 30 litres. The
Vd is a characteristic of each drug under
normal conditions and is altered under
conditions that affect distribution pattern of
the drug.

69. Protein binding of drugs
• Receptor protein with which drug interact to show
response are called as primary receptors.
• Binds to a protein in cells (tissue protein), but
the binding does not usually elicit a pharmacological
response. These are called secondary or silent
receptors
• Out side cells: plasma proteins, blood cells
• protein bound drug is neither metabolised nor
excreted nor it is active pharmacologically. A bound
drug is also restricted since it remains confined to a
particular tissue for which it has greater affinity.
Moreover, such a bound drug, because of its
enormous size, cannot undergo membrane
transport and thus its half-life is increased.

70. Implications of PPB of drugs
• Maintains steady free drug concentration
Eg 95% bound 5% free ratio maintained. Less
fluctuation in free drug concentration in blood
• Long acting (not available for metabolism)
• Displace endogenous protein bound substance eg
bilirubin by sulfonamides
• In hypoprotinemic states, free concn is more
- pregnancy, nephrotic syndrome, chronic liver
failure, malnutrition, anemia etc
• Displacement by competition warfarin 99: 1 vs
aspirin

71. Loading dose
• It takes 4-5 half life for the concentration of a
drug to produce the effect of a given dose of
a drug repeated at the interval of its half life.
• When the half life of a drug is more
- Eg 24 hours, it takes 4-5 days for the steady
state concentration to occur. Steady state
concentration of a drug occurs when the dose
excreted is equal to the dose given.

72. • Loading dose helps in the rapid development of the
needed concentration and its effect.
• Calculated thus
- Vd= D/C
- LD = target concentration x volume of distribution /
bioavailability = C x Vd
Therefore volume of distribution helps in the
calculation of loading dose of certain drugs in certain
indications
Eg digoxin in atrial fibrillation to control ventricular
rate
Vd = 7l/kg, C= 1ng/ml
Vd 7 x 60 kg = 420 L , C 1ng x 1000 ml = 1mcg/L
LD= 420 x 1 mcg = 0.42mg /1 1=F=IV= bioavailability
0.42mg/0.9 F=0.9 oral bioavaialbility

73. Excretion of drugs