Chemistry

1. PHARMACOKINETICS
“What the body does to the drug”
- ANIMA KASHYYAP

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

4. ADMET

5. 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

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 Lipinski 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

15. 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 .

16. 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×

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

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

19. 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

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

21. 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

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

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. 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

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

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

31. 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.

32. 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

33. 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

34. ADME - Summary

35. THANKYOU