ADME is the abbreviation for Absorption, Distribution, Metabolism and Excretion. ADME studies are designed to investigate how a chemical (e.g. a drug compound) is processed by a living organism. Toxicology tests are often a part of this process, yielding the acronym ADMET.

1. PHARMACOKINETICS - ADME
“What the body does to the
drug”
BY: SUBHAJIT MANDAL
REGISTRATION NO. RA1922255010004
M.PHARM (PHARMACOLOGY)
SRM COLLEGE OF PHARMACY
2019-2020
DATE: 5th /09/19

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
Elimination

3. ADME

4. Why drugs fail

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.

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

7. 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

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

9. The Process
• Absorption relies on
– Passage through membranes to reach the blood
– passive diffusion of lipid soluble species.

10. The Rule of Five – LIPINSKI’S RULE
Lipinski's rule of five also known as the Pfizer's rule of five or
simply the rule of five (RO5) is a rule of thumb to evaluate
druglikeness or determine if a chemical compound with a certain
pharmacological or biological activity has chemical properties and
physical properties that would make it a likely orally active drug in
humans.
Components of the rule
Lipinski's rule states that, in general, an orally active drug has no
more than one violation of the following criteria:
• No more than 5 hydrogen bond donors (the total number of
nitrogen–hydrogen and oxygen–hydrogen bonds)
• No more than 10 hydrogen bond acceptors (all nitrogen or
oxygen atoms)
• A molecular mass less than 500 daltons
• An octanol-water partition coefficient (log P) that does not
exceed 5

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

12. FACTORS AFFECTING
ABSORPTION

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
Which is 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) =
Amount of drug in body/plasma drug
concentration
• 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

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

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. 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.

32. • 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

33. Phase I (Drug Metabolism)
• Phase I biotransformation reactions
introduce or expose functional
groups on the drug with the goal of
increasing the polarity of the
compound.
• Although Phase I drug metabolism
occurs in most tissues, the primary
and first pass site of metabolism
occurs during hepatic circulation.

34. Phase II (Conjugation)
• 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.

35. 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

36. 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

37. 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

39. ADME - Summary