1. “What the body does to the drug”
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 discovery and development
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
Injection
Topical
Respiratory
Rectal
Oral

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

11. The Rule of Five - formulation
Poor absorption or permeation are
more likely when:
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.

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

13. First Pass Metabolism
Destroyed
in gut
Not
absorbed
Destroyed
by gut wall
Destroyed
by liver to
systemic
circulation
Dose
Bioavailability: the fraction of the administered dose reaching the 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. Amt of drug in body/plasma drug conc
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 ( 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
Excretion
Drug Metabolism
(Biotransformation)

27. Drug Metabolism More polar (water soluble) Drug Drug
The chemical modification of drugs with the overall goal of getting rid of the drug
Enzymes are typically involved in metabolism
Metabolism
Excretion
More polar
(water soluble)
Drug
Drug

28. METABOLISM
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

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. CYP family of enzymes
• 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:
• CYP1A • CYP2D6
• CYP2C • CYP2E1
• CYP2C • CYP3A4
In different people and different populations, activity of CYP oxidases differs.

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