1. Chapter 3 PHARMACOKINETICS “What the body does to the drug” Lei Wang
Department of Pharmacology

2. Absorption ：the movement of a drug from its site of administration into the circulation.
Distribution ：the movement of a drug leaving the bloodstream and going into the organs and tissues. A D M E 2

3. Metabolism(Biotransformation) : chemical alteration of the drug structure mediated by enzyme, primarily in the liver.
Excretion: the movement of drugs and their metabolites out of the body primarily by the kidneys.
Elimination: the combination of metabolism and excretion. A D M E

4. Transmembrane Transport of Drugs
Simple Diffusion
Specialized Transport
Filtration
Facilitated Diffusion
Active Transport

5. Simple Diffusion (Passive Diffusion )
Most drugs are transported across the membranes by passive diffusion
Diffuses across the membrane in the direction of drug’s concentration gradient
Diffusion rate is directly proportional to the gradient
No need of energy
No a carrier is involved

6. Simple Diffusion (Passive Diffusion )
Passive diffusion depends on the molecule's lipid solubility, size, degree of ionization, and the area of absorptive surface.

7. Cell Membrane Structure
Simple Diffusion (Passive Diffusion)
Cell Membrane Structure
Biological membranes are bilayer, phospholipids matrices containing cholesterol, protein, and other constituent.
The membranes are primarily lipid in nature.

8. “like dissolves like”
a solute will dissolve best in a solvent that has a similar chemical structure to itself.
Only lipid soluble drugs can dissolve in the lipid membrane and penetrate the membrane.
Lipid soluble drugs
Polar molecules and ions are not lipid soluble and cannot penetrate membranes by simple diffusion.
Water soluble drug

9. Effect of pH on passive diffusion
Simple Diffusion (Passive Diffusion)
Effect of pH on passive diffusion
Many drugs are weak acids or weak bases
Weak acids and weak bases exist in solution as a mixture of ionized and un-ionized forms
Weak Acid HA H A-
(unionized) (ionized)
(cross membrane)
Only the unionized (uncharged) form of a drug can cross cell membranes
Ionized = Water soluble
Nonionized = Lipid soluble

10. pKa : pH at which 50% of the drug is ionized and 50% is un-ionized.
Simple Diffusion (Passive Diffusion)
The proportion of unionized drug depends on the pKa (dissociation constant) of the drug and the environmental pH.
pKa : pH at which 50% of the drug is ionized and 50% is un-ionized.

11. Handerson-Hasselbalch Equation
Simple Diffusion (Passive Diffusion)
Handerson-Hasselbalch Equation
For acids (A)：
For bases (B)：

12. Effect of the environment pH on the degree of ionization
Simple Diffusion (Passive Diffusion)
Effect of the environment pH on the degree of ionization
A weak acid will be unionized when in an acidic environment, and a weak base will be unionized in a basic environment.
A weak acid will be ionized when in a basic environment, and a weak base drug will be ionized in an acidic environment.

13. An alkaline drug is preferentially ionized in an acidic environment.
Simple Diffusion (Passive Diffusion)
In the stomach (pH 2.0)，which will be better absorbed, a weak acid (pK 6.8) or a weak base (pK 7.1)?
A weak acid is most likely to be unionized when in an acidic environment
An alkaline drug is preferentially ionized in an acidic environment.
Weak acid

14. Most drugs are absorbed in the intestines
Simple Diffusion (Passive Diffusion)
Weak acids can also be absorbed more readily from the intestines than from the stomach, despite their greater ionization in the intestines
The greater surface area in the intestines outweighs the influence of greater ionization in the intestines.
Most drugs are absorbed in the intestines

15. Passive Tubular Reabsorption
The reabsorption of drug from the lumen of the distal convoluted tubules into plasma occurs by simple diffusion.
Urine pH determines the ionization state of a weak acid or base, and changes in urinary pH may markedly affect drug reabsorption and excretion.
Passive reabsorption of lipid-soluble, unionized drug
Passive Reabsorption
Ionized or polar metabolite

16. Simple Diffusion (Passive Diffusion)
Ion Trapping
Ion trapping occurs with weak acids and weak bases if there is a difference in pH on two sides of a membrane.
The ionized form of the drug will be trapped on one side of a membrane where the ionized form is predominant.
Ionized form
lipid
Nonionized form

17. NH3
NH3 H+ H+ H+
PH 7.4
NH3
PH 7.0 H+ H+ H+
NH3 H+
NH3
NH3
NH3

18. Once the unionized basic drug crosses the cell membrane to enter the cell, it becomes ionized
NH3 + H+ ⇌ NH4+
NH4+
PH 7.0
NH4+
NH4+
NH4+
NH4+
NH4+
NH4+
PH 7.4

19. Ion trapping results in basic drug’s accumulating in acidic bodily fluids and acidic drug’s accumulating in basic fluids. A- A- A-
NH4+
NH4+ A-
PH 7.0
NH4+ A-
NH4+
NH4+ A-
NH4+
PH 7.4

20. Filtration
Filtration is passage of drugs through aqueous pores in the membrane or through paracellular spaces.
Aqueous Diffusion

21. Filtration
Aqueous Diffusion
Water can cross cell membranes through aqueous pores.
Bulk flow of water can carry with it drug molecules.
Aqueous Diffusion
Bulk Flow

22. membrane by this process.
Aqueous Diffusion
Only those drugs whose molecular size is smaller than the diameter of the pores may pass through the aqueous pores.
Majority of cells have very small pores and drug with molecular weights (MW) exceeds 100 to 200 daltons are not able to penetrate.
Aqueous diffusion is restricted to drugs with low molecular weights; many drugs are too large to penetrate the
membrane by this process.

23. Paracellular Transport
Filtration
Paracellular Transport
Passing through the intercellular space between the cells.
Involved in capillaries.
Capillaries (except those in brain)
have large paracellular space and most drug can filter through these.
Be limited to unbound drug.
Be an important factor in filtration across glomerular membranes in the kidney.

24. Distribution
Plasma Protein Binding

25. Glomerular Filtration
Serum protein binding reduces filtration because plasma proteins are too large to be filtered.

26. Carrier-Mediated Membrane Transport
Be specific for the substrate (selectivity)
Carrier transport have arisen during evolution to carry naturally occurring molecules
In reality very few drugs can cross the membrane by this method
Be saturable.
Competitively inhibited by analogues which utilize the same transporter.

27. Facilitated Diffusion
It means the passage of drug across the biological membrane along the concentration gradient by the protein carrier mediated system also called as carrier mediated diffusion.
Example: Cephalexin undergo facilitated diffusion by an oligopeptide transporter protein located in intestinal

28. Active Transport
The process by which drugs pass across the biological membrane most often against their concentration gradient with the help of carriers along with the expenditure of energy.
In all cells, active transport usually accumulates some molecules that the cell needs, such as ions, glucose and amino acids.

29. Characteristics of active transport are:
Active Tubular Secretion
Characteristics of active transport are:
a. Saturability of the carrier
b. Competition between substrates for the carrier
penicillin
penicillin
penicillin
penicillin
probenecid
probenecid
Example:
OATs
OATs
OATs
OATs
OATs
OATs
Penicillin and Probenecid
Using acid pathway
Decreasing excretion of penicillin
Increasing action duration of penicillin

30. Transmembrane transport
ADME
Transmembrane transport
Simple diffusion
lipid solubility
Ion trapping
degree of ionization