1. Pharmacokinetics/Pharmacodynamics

2. Important Definitions
Pharmacokinetics: Quantitative description of the time course for the disposition of a drug in the body in terms of its absorption, distribution, metabolism and elimination.
Disposition: Where does the drug go?
Pharmacodynamics: The study of what a drug does in the body.

3. Disposition or Fate of a Drug
Drug at
Absorption Site
Drug in Body
Excreted Drug
Metabolite in
Body
Eliminated
Metabolite

4. Disposition or Fate of a Drug
Prescribed Dose
Absorption
Most Tissues:
Nonspecific binding
Protein Bound Free Drug
Plasma
Distribution
Target Tissue:
Receptor binding
Elimination
Metabolism
Renal
Excretion
Effect

5. Routes of Drug Administration
Intravenous (IV)
Subcutaneous/ Intramuscular (SC/IM)
Oral
Rectal
Inhalation

6. IV Administration IV Vascular Compartment Interstitial Water Cellular

7. SC/IM Administration SC/IM Dissolution in interstitial fluid Vascular
Compartment
Interstitial
Water
Cellular
Compartment

8. Oral Administration Oral Vascular Compartment Interstitial Water
Cellular
Compartment
Stomach
Liver
Portal
circulation
Duodenum

9. Aspirin: Where does most absorption occur? Stomach or intestine?
Stomach Intestine
pH =2
pH = 6

10. Aspirin (pKa = 3.5) COO- COO- Plasma membrane OCOCH3 OCOCH3 COOH COOH
pH =2
pH = 7.4

11. Biliary excretion
Enterohepatic circulation =
Opposed elimination

12. Oral Administration Oral Vascular Compartment Interstitial Water
Cellular
Compartment
Stomach
Liver
Portal
circulation
Duodenum

13. Factors Influencing Drug Distribution
pKa, lipid solubility, molecular weight
Blood flow to the tissue
Binding to macromolecules, such as plasma proteins and intracellular proteins
Anatomic barriers: Capillary endothelium, BBB, etc.

14. Biotransformation
Definition: Conversion of a xenobiotic to a more water soluble compound.
Biotransformation = metabolism
Biotransformation is catalyzed by enzymes in the liver and other tissues.

15. Tissue sources of metabolizing enzymes:
The liver is the richest source.
Tissues associated with the major routes of exposure: skin, lung, nasal mucosa, eye, gastrointestinal tract.
Others: Kidney, adrenal, pancreas, spleen, heart, brain, testis, ovary, placenta, plasma, erythrocytes, platelets, lymphocytes, aorta.

16. Biotransformation is accomplished by a small number of enzymes with broad substrate specificities.
Some xenobiotic metabolizing enzymes also metabolize endogenous compounds. Ex: bile salts, bilirubin.
Metabolizing enzymes are either:
1. Constitutive
2. Inducible – enzyme synthesis is induced by some external stimulus.

17. Biotransformation Reactions:
Phase I: Oxidation, reduction, hydrolysis
Reactions that expose or introduce a functional group.
Phase II: conjugation
Covalent linkage between the xenobiotic or one of its metabolites with a water-soluble, endogenous compound, e.g., glutathione.

18. Phase I Reactions

19. Phase II Conjugation

20. Biotransformation Reactions:
Phase I: Oxidation, reduction, hydrolysis
Imparts small increases in hydrophilicity.
Phase II: conjugation
Imparts large increases in hydrophilicity.

22. Inter-individual variations levels of P450’s

23. Examples of P450 Substrates, Inhibitors & Inducers

24. Other substances that can affect drug metabolism

25. Other substances that can affect drug metabolism

26. Elimination

27. Most important mode of elimination:
Most compounds eliminated
by kidneys
Polar and ionic compounds
eliminated more readily
At what urine pH are bases
absorbed?
excreted?

28. Importance of Elimination in PK

29. Elimination Half-Life:
t1/2 = The time required for the plasma concentration (or total body stores) of a drug to fall to half of its initial concentration.

30. Realistically, with repetitive dosing:
Cmax
[Drug]
Cmin
Hours after administration