The document discusses pharmacokinetics, which is the study of drug disposition in the body, encompassing absorption, distribution, metabolism, and excretion (ADME). It highlights the significance of pharmacokinetic studies in drug development and patient safety, noting that unsuccessful drug development can lead to toxic accumulation or ineffective treatment. The document outlines various factors influencing drug absorption, metabolism phases, and elimination processes.

1. Pharmacokinetics and it’s
Importance
By-
Prof. Vedanshu R. Malviya
(M.Pharm (Pharmaceutics), Ph.d (Pursuing)
Dr. Rajendra Gode Institute of Pharmacy, Amravati-444901

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

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. 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)

6. Why drugs fail

7. 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.

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

9. 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

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

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

12. 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:

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

14. 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

22. 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

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

24. 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.

25. 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

26. 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.

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

28. 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

29. •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

30. 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

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

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

33. 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.

34. • 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

36. 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)

37. 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.

38. 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

39. 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

40. 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

41. 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

42. ADME - Summary