The document outlines the pharmacokinetics of drugs, detailing the processes of absorption, distribution, metabolism, and excretion (ADME). It emphasizes the significance of pharmacokinetics studies in drug development and the factors influencing drug efficacy and toxicity. Additionally, it discusses drug metabolism phases and the role of enzymes, particularly the cytochrome P450 family, in drug biotransformation.

1. PHARMACOKINETICS
“What the body does to the drug”

2. 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. ADMET

4. DRUG R&D
Drug discovery and development
•10-15 years to develop a new medicine
•Likelihood of success: 10%
•Cost $800 million – 1 billion dollars (US)

5. Why drugs fail

6. 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.

7. Routes Of
Administration
Routes Of Drug
Administration
Enteral
Parenteral
Oral
Injection Rectal
Respiratory
Topical

8. Absorption
 The process by which drug proceeds from
the site of administration to the site of
measurement (blood stream) within the
body.
 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

9. IV vs Oral
I.V Drug Oral Drug
Immediately Delayed
completely incomplete

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

11. The Rule of Five -
formulation
 There are more than 5 H-bond donors.
 The molecular weight is over 500.
 The LogP is over 5.
 There are more than 10 H-bond
acceptors.
Poor absorption or permeation are
more likely when:

12. Absorption & Ionization
Non-ionised
drug
More lipid soluble drug
Diffuse across
cell
membranes more
easily

13. 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

14. 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
.

15. Toxicity
 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
100× 10×

16. Distribution
 The movement of drug from the blood
to and from the tissues

17. DISTRIBUTION
 Determined by:
 • partitioning across various membranes
 •binding to tissue components
 •binding to blood components (RBC,
plasma protein)
 •physiological volumes

18. DISTRIBUTION
 All of the fluid in the 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

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

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

21. Factors affecting drugs Vd
 Blood flow: rate varies widely as function of tissue
Muscle = slow
Organs = fast
 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

22. Blood Brain Barrier
•Disruption by osmotic
means
•Use of endogenous
transport systems
•Blocking of active
efflux transporters
• Intracerebral
implantation
•Etc

23. 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.

24. Physiochemical properties-
Po/w
 The Partition coefficient (Po/w) and 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

25. 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.

26. Elimination
 The irreversible removal of the
parent drugs from the body
Elimination
Drug Metabolism
(Biotransformation)
Excretion

27. 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

28. •From 1898 through 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

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

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

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

32. The Most Important
Enzymes
 Microsomal cytochrome P450
monooxygenase family of enzymes, which
oxidize drugs
 Act on structurally unrelated drugs
 Metabolize the widest range of drugs.

33. • 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:
• CYP1A2 • CYP2D6
• CYP2C9 • CYP2E1
• CYP2C19 • CYP3A4
In different people and different populations,
activity of CYP oxidases differs.
CYP family of enzymes

35. Inhibitors and inducers of
microsomal enzymes
Inhibitors: cimetidine prolongs action of drugs or inhibits
action of those biotransformed to active agents (pro-drugs)
Inducers: barbiturates, carbamazepine shorten action of
drugs or increase effects of those biotransformed to active
agents
Blockers: acting on non-microsomal enzymes (MAOI,
anticholinesterase drugs)

36. Phase II
 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.

37. 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

38. 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

39. 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

40. 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

41. ADME - Summary