Pharmacokinetics Drug Transportation

1. Pharmacokinetics
Drug Transportation
Dr.Muhammad Usman Khalid
DPT(SMC),MS-NMPT(RIU)

2. Drug permeation
per; through + meare ; to pass
To spread itself through something
To pass through the pores or
interstices of

3. Drug permeation
It refers to the movement of
drug molecules in the body
Absorption --- from its site of
administration into the blood
Distribution --- To the site of
action between different
compartments of the body
Excretion --- out of the body

7. Drug permeation
• The absorption, distribution,
metabolism and excretion of a
drug all involve its passage
across cell membranes

8. 12/23/2012

9. Passage of drugs across cell membrane
•Passive diffusion
•Specialized
transport

10. Specialized transport
• Carrier transport
oActive transport
oFacilitated diffusion
• Pinocytosis (endocytosis)
• Exocytosis
o The principal mechanism of transmitter release in the peripheral and CNS

11. Endocytosis

12. Greek ; pinein (to drink)
for very large molecules -- proteins, ATP
requiring
Pinocytosis contributes little to the transport of drugs
Vitamin B12 + intrinsic proteins across the gut wall
Iron + transferrin into Hb –synthesizing red cells
Insulin crosses the BBB

13. Pinocytosis contributes little to
the transport of drugs
• Vitamin B12 + intrinsic proteins
across the gut wall
• Iron + transferrin into Hb –
synthesizing RBC
• Insulin crosses the BBB

14. Specialized transport
• Carrier transport
oActive transport
oFacilitated diffusion
• Pinocytosis (endocytosis)
• Exocytosis
o The principal mechanism of transmitter release in the peripheral and CNS

16. •Carrier transport is not
governed by Fick's law of
diffusion and is capacity
limited

17. Active transport
Saturable &
Inhibitable
may move a molecule against
its diffusion gradient e.g. sodium pump

18. Saturable and inhibitable

19. Facilitated diffusion
Saturable &
Inhibitable
transports molecules
down a diffusion gradient
- aa from GI lumen in to epithelial
cells

20. Sites where
carrier-mediated drug
transport is important
The BBB
The GIT
The renal tubules
The biliary tract
The placenta

21. Special carriers
• Selective membrane carriers -- Peptides, aa, glucose
o Many drugs also use these carriers
• Less selective membrane carriers
Binds ATP
o P-glycoprotein
o Multidrug resistance-associated protein (MRP) transporter
Do not bind protein but use ion gradient for
transport energy
o uptake of neurotransmitters across nerve ending

22. P-glycoprotein
• The drug transporter --- Specialized for expelling foreign
molecules
• It is present in renal tubular brush border membrane,
in bile canaliculi, in astrocytes foot processes in
brain microvessels, and in the GIT
• The drug transporter responsible for multidrug resistance
in the neoplastic cells

24. Passive diffusion
• Passive movement of
molecules from an area of
greater concentration to an
area of lower concentration

28. Passive diffusion
• Lipid soluble drugs --- By
diffusion directly through the
lipid
• Water soluble (lipid insoluble)
drugs --- By diffusion through
the aqueous pores formed by
special proteins “aquaporins”
that traverse the lipid

29. Lipid soluble drugs
Water soluble drugs
(Lipid insoluble drugs)
Aquaporins
diameter – 0.4 nm
Drugs usually exceeds 1 nm

30. Water soluble drugs
(Lipid insoluble drugs)
Aquaporins
Diameter – 0.4 nm
Drugs usually exceeds 1 nm

31. Absence of pores in
capillaries of
•Brain
•Testis

32. Fick’s law of diffusion
Area X Permeability coefficient
Flux = (C1 – C2) X ---------------------------------
Thickness
Flux = molecules per unit time
C1 = higher concentration
C2 = lower concentration
Area = Area of diffusion

33. • Surface area --- Drug absorption is faster from organs
with large surface area
o Small intestine >> stomach
o Lungs
• Thickness of the membrane --- drug absorption is
faster from organs with thin membrane barriers such as
the lung compared to those with thick barriers such as
the skin.

34. Permeability coefficient,
P
• The lipid-aqueous coefficient / Partition
coefficient (P oil/water)
• The ratio of a drug’s solubility in lipid
(membrane) as compared to water (ECF)
• A large P oil/water means that a
drug is highly soluble in lipid
and will cross membrane
easily.

35. The ability of the drugs to move from
aqueous to lipid medium and vice versa
depends upon
•Ionization of drugs
(+ or -)
•pH of the medium

36. The ability of the drugs to move from
aqueous to lipid medium and vice versa
depends upon
•Ionization of drugs
oThe ionized drug molecule (+ or -)
attracts water dipoles and results in a
polar water soluble & lipid insoluble
complex.
•pH of the medium

37. Solubility & ionization of
drugs
•A drug passes
through
membranes more
readily if it is
uncharged

38. Solubility & ionization of
drugs
•Ionization of drugs may
markedly reduce their lipid
solubility and to permeate
membranes
o An ionized molecule is relatively water soluble and lipid-insoluble

39. Weak acids

40. Weak base

41. Solubility & pH of medium
• Weak acid will be in the
lipid soluble form at acid
pH
• Basic drug will be in the
lipid soluble form at
alkaline pH

42. Effect of the pH of the
medium
• Most drugs are either weak
acids or weak bases; their
state of ionization varies
with pH according to the
Henderson-Hasselbalch
equation

43. Weak acid
• A weak acid is a neutral molecule
that can reversibly dissociates
into an anion and a proton
HA A- + H+
C8H7O2COOH C8H7COO- + H+
neutral aspirin Aspirin anion proton
• Aspirin --- pKa = 3.5

45. Weak base
• A weak base is a neutral
molecule that can form a cation
by combining with a proton
C12H11C1N3NH3+ C12H11C1N3NH2 + H+
Pyremethamine cation neutral pyremathamine proton
BH+ B +
H+

46. Weak base

47. The Henderson-
Hasselbalch equation
[unpronated species]
pH = pKa + log -------------------------------------
[pronated species]

48. Weak acids
RCOOH = RCOO- + H+
(Protonated) (Un
protonated)
[A-]
pH = pKa + log --------------
[HA]

49. Weak base
RNH 3
+ = RNH2 +
H+
(Protonated) (Unprotonated)
[A-]
pH = pKa + log --------------
[HA]

50. The Henderson-
Hasselbalch equation
[unpronated species]
pH = pKa + log ----------------------------------
[pronated species]
[A-]
For acids: pH = pKa + log -------------
[HA]
[B]
For bases: pH = pKa + log ----------
[BH+]

51. Tissue
pH 7.4
Stomach lumen
pH 1-3
The pH in the stomach allows for the passive absorption
of acids, but not weak bases.

52. Duodenal lumen
pH 5-7
Tissue
pH 7.4
The higher pH in the small intestine allows for the pas
absorption of weak bases but not weak acids.

53. •The lower the pKa
the stronger the acid
•Higher pKa the
stronger the base

54. When pH of a solution is the same as the pKa of a drug
within it then the drug is 50 % ionized and 50 % union

55. When pH is less than
pKa
the pronated forms HA
and BH+ predominate

56. When pH is greater than
pKa
the depronated forms A-
and B predominate

57. •The uncharged form is
more lipid soluble
•More of a weak acid will
be in the lipid soluble
form at acidic pH
•More of a basic drug will
be in the lipid soluble
form at alkaline pH

58. pH partition
• Weak acids tend to accumulate
in compartments of relatively
high pH
• Weak bases tends to
accumulate in compartments of
relatively low pH

59. Clinical application
• To increase the urinary
excretion of acidic drugs we
make the urine alkaline.
• To increase the urinary
excretion of alkaline drugs
we make the urine acidic.

60. Clinical application
• Almost all drugs are filtered at the glomerulus
• if a drug is in lipid soluble form it will be reabsorbed by
the renal tubules by simple passive diffusion.
• To increase excretion of a drug , it is important to prevent
its reabsorption from the tubules.
• Weak acids will be excreted faster in alkaline urine
• Weak bases will be excreted faster in acid urine

61. Clinical application ---
Aspirin toxicity
• Bicarbonate & actazolamide each ↑ urine pH and
hence ↑ salicylate elimination, but bicarbonate reduce
whereas acetazolamide increases distribution of
salicylate to the CNS
o (I/V Na HCO3) causes ↑in plasma pH --- weakly acidic is extracted from the CNS
to plasma.
o Acetazolamide -- ↓ plasma pH --- causes weakly acidic drugs to become
concentrated in the CNS --- ↑neurotoxicity

62. Urine pH and drug
elimination
•Ionized drugs get
trapped

63. Ionized drugs get
trapped
Weak base Weak acids
• Trapped in acidic
environment
• Amphetamine
• Treat overdose
with ammonium
chloride
o RNH3
+ ↔ RNH2 + H+
(Trapped) (lipid soluble)
• Trapped in basic
environment
• Phenobarbital,
methotrexate, TCAs,
aspirin
• Treat overdose with
bicarbonate
o RCOOOH ↔ RCOO- +
H+
(Lipid soluble) ↔
(trapped)

64. Sites of pH difference in
the body
• The body fluids in which pH differences from blood pH
may cause trapping or reabsorption are
• Stomach and small intestine
• Breast milk
• Aqueous humor
• Vaginal and prostatic secretions

65. Ion trapping
• Aspirin (pKa 3.5) in stomach ( pH 1-1.5)is unionized
and lipid soluble and diffusible and therefore readily
absorbed
• Aspirin enters the gastric epithelial cells (pH 7.4) will
ionize because of higher pH and will be localized there --
- “ion trapping” --- concentrated and harms the gastric
mucosa

66. • To determine how much drug will be
found on either side of a membrane that
separates two compartments that differ in
pH e.g.,
•Stomach pH (1-1.5)
and
and blood (pH 7.4)

67. Factors influencing
absorption
• Effect of pH on drug absorption
• Blood flow to absorption site
• Total surface area available for absorption
• Contact time at the absorption surface
• Expression of G protein

68. THANK YOU