Pharmacokinetics

1. Pharmacokinetics
(Pharmacology & Therapeutics-1)
Lecture By
Dr. Syed Baqir Raza Naqvi
(BSc, Pharm-D, M. Phil-Pharmacology)
Nazar College of Pharmacy
DAKSON Institute of Health Sciences, Islamabad
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2. PHARMACOKINETICS
“What the body does to the drug”
2

3. Pharmacokinetics (PK)
 The study of the disposition of a drug
 The disposition of a drug includes the processes
of ADME
 Absorption
 Distribution
 Metabolism
 Excretion
 Toxicity
Elimination
3

4. ADMET
4

5. 5

6. DRUG R&D
Research and Development
Drug discovery and development
•10-15 years to develop a new medicine
•Likelihood of success: 10%
•Cost $800 million – 1 billion dollars (US)
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7. Why drugs fail
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8. Importance of PK studies
 Patients may suffer:
 Toxic drugs may accumulate
 Useful drugs may have no benefit because doses
are too small to establish therapy
 A drug can be rapidly metabolized.
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9. Routes Of Administration
Routes Of Drug
Administration
Enteral
Parenteral
Oral
Injection Rectal
Respiratory
Topical
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10. 1. Absorption
 The process by which drug proceeds from the site of
administration to the site of measurement/Action
(blood stream) within the body.
Importance
 Necessary for the production of a therapeutic effect.
 Most drugs undergo gastrointestinal absorption. This
is extent to which drug is absorbed from gut lumen
into portal circulation.
 Exception: IV drug administration 10

11. IV v/s Oral Absorption
I.V
Drugs
Oral
Drugs
Immediately Delayed
completely incomplete
11

12. Mechanisms of drug absorption
1. Simple diffusion / passive diffusion.
2. Facilitated diffusion.
3. Active transport.
4. Phagocytosis (Endocytosis).
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13. 13

14.  Absorption relies on
 Passage through membranes to reach the blood
 passive diffusion of lipid soluble species.
The Process
14

15. water soluble drug (ionized
or polar) is readily
absorbed via aqueous
channels or pores in cell
membrane.
Lipid soluble drug (non-
ionized or non polar) is
readily absorbed via cell
membrane itself.
15

16. Characteristics
 common way of absorption.
 Occurs along concentration gradient.
(Higher conc. To lower concentration)
 Non selective Process.
 It Requires no energy.
 No carrier is needed.
 Depends on lipid solubility.
 Depends on pH of medium.
16

17. 17

18. PKa of the drug
(Dissociation or ionization constant):
pH at which half of the substance is ionized
& half is unionized.
pH of the medium
Affects ionization of drugs.
 Weak acids  best absorbed in stomach.
 Weak bases  best absorbed in intestine.
18

19. II- Facilitated diffusion
 Some drugs can enter the cell
through specialized trans
membrane carrier proteins that
facilitate the passage of large
molecules.
These carrier proteins undergo conformational changes, allowing
the passage of drugs into the interior of cells and moving them from
an area of high concentration to an area of low concentration.
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20. • It doesn't require
energy.
• May be inhibited
by compounds
that compete for
carrier.
II- Facilitated diffusion (Cont.)
20

21. Occurs against concentration
gradient. (Lower to Higher)
Requires carrier and energy.
It is Specific
It is Saturable.
Example: Iron absorption,
Uptake of levodopa by brain.
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22. 22

23. 23

24. 24

25. 25

26. Endocytosis
It involves engulfment of a drug
by the cell membrane and
transport into the cell by
pinching off the drug filled
vesicles.
Exocytosis
expulsion of membrane-bound
particles.
High molecular weight drugs or
Highly lipid insoluble drugs.
26
Exocytosis

27. There are two types of endocytosis
2. Phagocytosis (cell eating):
large particles, (visible with light
microscope) are invaginated into the
cell (i.e: white blood cells ‘eat’
bacteria).
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1. Pinocytosis (cell drinking):
small molecules are ingested and a
vesicle is immediately formed. This
is seen in small intestine cells (villi).

28. Factors Affecting Absorption
 Effect of pH on drug absorption (Like dissolves like)
 Blood flow to the absorption site
 Total surface area available for absorption
 Contact time at the absorption surface
 Expression of P-glycoprotein
 Bioavailability 28

29. The Rule of Five - formulation
 There are more than 5 H-bond donors.
 The molecular weight is over 500.
 There are more than 10 H-bond acceptors.
Poor absorption or permeation are
more likely when:
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30. Absorption & Ionization
Non-ionised drug
More lipid soluble drug
Diffuse across cell
membranes more
easily
30

31. Bioavailability
 Bioavailability is the rate and extent to
which an administered drug reaches the
systemic circulation.
 For example, if 100 mg of a drug is administered
orally and 70 mg is absorbed unchanged, the
bioavailability is 0.7 or 70%.
 Importance: Important for calculating drug
dosages for non intravenous routes of
administration. 31

32. Determination of
Bioavailability
 A drug given by the
intravenous route will have
an absolute bioavailability of
1 (F=1 or 100%
bioavavailable)
 While drugs given by other
routes usually have an
absolute bioavailability of
less than one.
 The absolute bioavailability is
the area under curve (AUC)
non-intravenous divided by
AUC intravenous
.
32

33. Factors affecting Bioavailability
 Solubility of the drug
 Chemical instability
 Nature of the drug formulation
 First-pass hepatic metabolism
33

34. First Pass Metabolism
 Bioavailability: the fraction of the administered dose reaching the
systemic circulation
Dose
Destroyed
in gut
Not
absorbed
Destroyed
by gut wall
Destroyed
by liver
to
systemic
circulation
34

35. Bioequivalence
 Two drug formulations are bioequivalent if
they show comparable bioavailability and
similar times to achieve peak blood
concentrations.
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36. Therapeutic equivalence
 Two drug, if they are pharmaceutically equivalent which
means, they have the same dosage form, contain same
active ingredient, same route of administration with
similar clinical and safety profiles.
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37. Therapeutic Index
 The therapeutic index is
the degree of separation
between toxic and
therapeutic doses.
 Relationship Between Dose,
Therapeutic Effect and Toxic
Effect. The Therapeutic
Index is Narrow for Most
Cancer Drugs
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38. 38

39. 39

40. 40

41. Toxicity
41
100× 10×

42. 2. Distribution
 The movement of drug
from the blood
to and from the tissues.
 It is the process by
which a drug reversibly
leaves the bloodstream
and enters the
interstitium
(extracellular fluid) and
the tissues.
42

43. DISTRIBUTION
 Determined by:
 • Partitioning across various
membranes.
 •Binding to tissue
components.
 •Binding to blood
components (RBC, plasma
protein).
 •Physiological volumes. 43

44. DISTRIBUTION
 All of the fluid in body (referred to as the total body
water), in which a drug can be dissolved, can be roughly
divided into three compartments;
 Intravascular (blood plasma found within blood vessels)
 Interstitial/tissue (fluid surrounding cells)
 Intracellular (fluid within cells, i.e. cytosol)
 The distribution of a drug into these compartments is
dictated by it's physical and chemical properties.
..44

45. TOTAL BODY WATER
Vascular
3 L
4% BW
Extravascular
9 L
13% BW
Intracellular
28 L
41% BW
45

46. Distribution
 volume of distribution (Vd) =
Amt. of drug in body/plasma drug conc.
46
DRUG Vd (L)
cocaine 140
clonazepam 210
amitriptyline 1050
amiodarone ~5000
VOLUME OF DISTRIBUTION FOR
SOME DRUGS (VD/L)

47. Factors affecting drugs Vd
1. Blood flow
 Rate varies widely as function of tissues;
Muscle = slow Organs = fast
2. Capillary structure
•Most capillaries are “leaky” and do not impede
diffusion of drugs.
•Blood-brain barrier formed by high level of tight
junctions between cells.
•BBB is impermeable to most water-soluble drugs.
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48. Blood Brain Barrier
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49.  3. Plasma Protein Binding
 Many drugs bind to plasma
proteins in the blood
steam.
 Plasma protein binding
limits distribution.
 A drug that binds plasma
protein diffuses less
efficiently, than a drug that
doesn’t (free drug).
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Factors affecting drugs Vd

50. Physiochemical properties-
Po/w
 4. Physiochemical properties-(Po/w)
 The Partition coefficient (Po/w) can be used to
determine where a drug likes to go in the body.
 Any drug with a Po/w greater than 1 (diffuse through
cell membranes easily) is likely be found throughout all
three fluid compartments.
 Drugs with low Po/w values (meaning that they are
fairly water-soluble) are often unable to cross and
require more time to distribute throughout the rest of
the body.
50

51. Physiochemical Properties-
Size of drug
The size of a drug also dictates where it can go in the body.
•Most drugs : 250 and 450 Da MW
•Tiny drugs (150-200 Da) with low Po/w values like caffeine can
passively diffuse through cell membranes.
•Antibodies and other drugs range into the thousands of daltons.
•Drugs >200 Da with low Po/w values cannot passively cross
membranes- require specialized protein-based transmembrane
transport systems- slower distribution.
•Drugs < thousand daltons with high Po/w values-simply diffuse
between the lipid molecules that make up membranes, while anything
larger requires specialized transport.
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52. Elimination
 The irreversible removal of the parent
drugs from the body.
Elimination
Drug Metabolism
(Biotransformation)
Excretion
52

53. 1. Drug Metabolism
 The chemical modification of drugs with the
overall goal of getting rid of the drug.
 Enzymes are typically involved in metabolism.
Drug
Metabolism
More polar
(water soluble)
Drug
Excretion
53

54. Biotransformation Mostly
occurs in the liver because
all of the blood in the body
passes through the liver.
54

55. •Example: From 1898 to 1910 heroin was marketed as a
non-addictive morphine substitute and cough medicine for
children. Bayer marketed heroin as a cure for morphine
addiction.
•Heroin is converted to morphine when metabolized in the
liver.
METABOLISM
55

56. Phases of Drug Metabolism
Phase-I Reactions
 Conversion of parent compound into a more polar
(=hydrophilic) metabolite by adding or unmasking
functional groups (-OH, -SH, -NH2, -COOH, etc.)
 For example; Oxidation.
 Often these metabolites are inactive.
 May be sufficiently polar to be excreted readily.
56

57. Phases of metabolism
Phase-II Reactions
 Conjugation with endogenous substrate to
further increase aqueous solubility.
 For Example, Conjugation with glucoronide,
sulfate, acetate, amino acid.
57

58. 58

59. Phase-I Reactions
 These include
 Amine oxidation (eg., oxidation of catecholamines or
histamine),
 Alcohol dehydrogenation (for example, ethanol
oxidation), Esterases (for example, metabolism of aspirin in
the liver),
 Hydrolysis (for example, of procaine).
59

60. Enzymes involved in
Biotransformation
 Microsomal Cytochrome P450
(CYP450) mono-oxygenase family
of enzymes, which oxidize drugs.
 Act on structurally unrelated
drugs.
 Metabolize the widest range of
drugs.
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61. • Found in liver, small intestine, lungs, kidneys, placenta.
• Consists of > 50 isoforms.
• Major source of catalytic activity for drug oxidation.
• It’s been estimated that 90% or more of human drug
oxidation can be attributed to 6 main enzymes:
• CYP-1A2 • CYP-2D6
• CYP-2C9 • CYP-2E1
• CYP-2C19 • CYP-3A4
In different people and different populations, activity of CYP oxidases
differs.
CYP family of enzymes
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62. Inhibitors and inducers of
microsomal enzymes
Inhibitors: Cimetidine prolongs action of drugs or
inhibits action of those bio-transformed to active agents
(pro-drugs).
Inducers: Barbiturates, carbamazepine shorten
action of drugs or increase effects of those bio-
transformed to active agents.
Blockers: acting on non-microsomal enzymes (MAOI,
anticholinesterase drugs).
62

63. 63

64. Phase-II Reactions
 Main function of phase I reactions is to prepare
chemicals for phase II metabolism and subsequent
excretion.
 Phase II is the true “detoxification” step in the
metabolism process.
64

65. Phase II reactions
 Conjugation reactions
 Glucuronidation (on -OH, -COOH, -NH2, -SH groups)
 Sulfation (on -NH2, -SO2NH2, -OH groups)
 Acetylation (on -NH2, -SO2NH2, -OH groups)
 Amino acid conjugation (on -COOH groups)
 Glutathione conjugation (to epoxides or organic halides)
 Fatty acid conjugation (on -OH groups)
 Condensation reactions. 65

66. Glucuronidation
Conjugation to a-d-glucuronic acid
 Quantitatively the most important phase II pathway for drugs
and endogenous compounds.
 Products are often excreted in the bile.
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67. Phase I and II - Summary
 Products are generally more water soluble.
 These reactions products are ready for (renal) excretion.
 There are many complementary, sequential and
competing pathways.
 Phase I and Phase II metabolism are a coupled
interactive system interfacing with endogenous
metabolic pathways.
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68. Excretion
 The main process that body eliminates "unwanted"
substances.
 Most common route - biliary or renal.
 Other routes - lung (through exhalation), skin
(through perspiration) etc.
 Lipophilic drugs may require several metabolism
steps before they are excreted.
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69.  Glomerular Filtration.
 Proximal tubular secretion.
 Distal tubular reabsorption.
69
Excretion

70. Drug clearance
 Drug clearance may also occur via the intestines, bile,
lungs, and breast milk, among others.
 The lungs are primarily involved in the elimination of
anesthetic gases (for example, isoflurane).
 Excretion of most drugs into sweat, saliva, tears, hair,
and skin occurs only to a small extent.
 Elimination of drugs in breast milk may expose the
breast-feeding infant to medications and/or
metabolites being taken by the mother.
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71. 71

72.  Total body clearance and drug half-life are important
measures of drug clearance that are used to optimize
drug therapy and minimize toxicity.
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Drug clearance

73. ADME - Summary
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74. Thank you !
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