Pharmacokinetics for pharmacy students

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