1. Lecture 7 PHARMACOKINETICS

2. Aspects of Drug Pharmacokinetics (ADME)
Drug at site
of administration
Absorption
Drug in plasma
Distribution
Drug/metabolites
in tissues
Metabolism
Elimination
Drug/metabolites
in urine, feces, bile

4. Absorption

5. Absorption Definition :
The process of movement of unchanged drug from the site of administration to systemic circulation.
The ultimate goal is to have the drug reach the site of action in a concentration which produces a pharmacological effect.
No matter how the drug is given (other than IV) it must pass through a number of biological membranes before it reaches the site of action.

6. LIPID BILAYER
KLECOP, Nipani
08/10/2010

7. Factors Affecting GIT Absorption
Blood Flow To Absorptive Site:
Greater blood flow raises absorption
Intestine has greater BF than stomach
Total Surface Area of Absorptive Site:
Intestinal microvilli increases surface area to fold that of the stomach favoring intestinal absorption
Contact Time at Absorptive Site:
Diarrhea reduces absorption
Accelerated gastric emptying→ faster delivery to intestinal large surface → increased absorption

8. Factors Affecting GIT Absorption
Food: Presence of food in the gut reduces/delays drug absorption from GIT
Increased splanchnic blood flow during eating increases drug absorption
Ionized drugs as tetracycline can form insoluble complexes with Ca2+ in food/milk.
Formulation Factors:
Solid dosage forms dissolution & solubility are essential
Aqueous solutions are absorbed more quickly than tablets or suspensions

9. PHYSICOCHEMICAL FACTORS
Drug transported by passive diffusion depend upon:
dissociation constant, pKa of the drug
pH at absorption site.
lipid solubility, K o/w. Polarity estimates partition coefficient. The greater the lipid solubility – the faster the rate of diffusion
Most drugs are either weak acids or weak bases whose degree of ionization is depend upon pH of biological fluid.

10. For a drug to be absorbed, it should be unionized and the unionized portion should be lipid soluble. Only non-ionized fraction of drugs (acids or bases is absorbed
The fraction of drug remaining unionized is a function of both
Dissociation constant (pKa) and pH of solution.

11. HENDERSON HASSELBATCH EQUATION
For acid,
pKa - pH = log[ Cu/Ci ]
For base,
pKa – pH = log[ Ci/Cu ]
Eg. Weak acid aspirin (pKa=3.5) in stomach (pH=1) will have > 99%of unionized form so gets absorbed in stomach
Weak base quinine (pKa=8.5) will have very negligible unionization in gastric pH so negligible absorption
Several prodrugs have been developed which are lipid soluble to overcome poor oral absorption of their parent compounds.

12. DIFFUSION THROUGH MEMBRANES
Absorption facts:
Smaller molecules penetrate more rapidly.
The membrane is Highly permeable to O2, CO2, NO and H2O .
Large polar molecules – sugar, amino acids, phosphorylated intermediates – poor permeability. These are essential for cell function, and thus must be actively transported

13. MOVEMENT OF SUBSTANCES ACROSS CELL MEMBRANES
KLECOP, Niani

14. MECHANISMs OF DRUG ABSORPTION
Passive diffusion
Carrier- mediated transport
a) Facilitated diffusion
b) Active transport
PINOCYTOSIS
KLECOP, Nipani
08/10/2010

15. PASSIVE DIFFUSION Also known as non- ionic diffusion.
It depends on the difference in the drug concentration on either side of the membrane.
Absorption of 90% of drugs.
The driving force for this process is the concentration or electrochemical gradient.

16. 2) CARRIER MEDIATED TRANSPORT MECHANISM
Involves a carrier (a component of the membrane) which binds reversibly with the solute molecules to be transported to yield the carrier solute complex which transverses across the membrane to the other side where it dissociates to yield the solute molecule
The carrier then returns to its original site to accept a fresh molecule of solute.
There are two types of carrier mediated transport system:
a) facilitated diffusion
b) active transport

17. a) Facilitated diffusion
This mechanism driving force is concentration gradient.
In this system, no use of energy is involved (down-hill transport), therefore the process is not inhibited by metabolic poisons that interfere with energy production.

18. b) Active transport More important process than facilitated diffusion.
The driving force is against the concentration gradient or uphill transport.
Since the process is uphill, energy is required in the work done by the barrier.
As the process requires energy, it can be inhibited by metabolic poisons that interfere with energy production.

19. Drug Absorption Active vs. Passive
Active transport:
Carrier-mediated
Energy-dependent
Against conc gradient
Shows carrier saturation kinetics
Passive transport
Energy-independent
No carrier involved
Along conc gradient
No saturation kinetics
ATP
Carrier-mediated energy-dependent active transport
ADP
+ Pi
Passive diffusion of a water-sol drug via aqueous channel AH B
Passive diffusion of a lipid-sol drug A-
BH+

20. 3) Pinocytosis
This process is important in the absorption of oil soluble vitamins & in the uptake of nutrients.

21. Bioavailability
the proportion of the drug in a dosage form available to the body
Fraction of a drug reaching systemic circulation in chemically unchanged form after a particular route
First pass metabolism, i.e., rapid hepatic metabolism, reduces bioav. (lidocaine, propranolol, nitrates)

22. BIOAVAILABIITY Time Injected Dose Serum Concentration Oral Dose
Drug solubility
Chemical instability in gastric pH (penicillin G, insulin)
Drug formulation: Standard & SR formulations
Bio = AUC oral/AUC IV x 100
Injected Dose
Serum Concentration
Oral Dose
Time

23. Therapeutic success of a rapidly & completely absorbed drug.
Not only the magnitude of drug that comes into the systemic circulation but also the rate at which it is absorbed is important this is clear from the figure.
Plasma
Drug
Conc.
Minimum effective conc.
Therapeutic failure of a slowly absorbed drug.
Subtherapeutic level
Time