1. Pharmacology Department
Pharmacokinetics II:
Bioavailability and Distribution
Prof. Hanan Hagar
Pharmacology Department

2. Distribution What student should know Major body fluid compartments
Concept of compartments.
Apparent volume of distribution (vd).
Plasma protein binding.
Tissue binding.
Redistribution

3. Distribution
Is the process by which drugs leave blood circulation and enters the interstitium and/or the cells of the tissues.

4. Absorption & distribution
Elimination
Sites of
Administration

6. - Plasma ( 5 % of body weight = 4 liters ).
The major body fluid compartments are
Extracellular fluid (22%)
- Plasma ( 5 % of body weight = 4 liters ).
- Interstitial fluid ( 16 % = 10 liters).
- Lymph ( 1 % ).
Intracellular fluid ( 35 % )
fluid present inside all cells in the body (28 L).
Transcellular fluid ( 2%)
cerebrospinal, intraocular, synovial, peritoneal, pleural & digestive secretions.

7. (60% of body weight in 70-kg individual)
Total body fluids
(60% of body weight in 70-kg individual)
Plasma (4 L)
Interstitial fluids (10 L)
Intracellular volume ( 28 L)
Total body
Fluids
(42 Liters)

8. Apparent Volume of Distribution (Vd)
is the ratio of drug amount in the body to the concentration of drug in blood
Vd (L)= total amount of drug in body (mg)
concentration in blood (mg/L)
Large Vd = means long duration of action

9. FACTORS AFFECTING DISTRIBUTION
1.Cardiac output and blood flow.
2. Physiochemical properties of the drug.
Molecular weight
Pka.
Lipid solubility.
3. Capillary Permeability
4. Plasma protein binding
5. Tissue binding.

10. Blood flow to organs
The greater the blood flow to tissues, the more distribution that occurs from plasma to interstitial fluids.
Drugs distribute more rapidly to brain, liver and kidney > more than skeletal muscles & fat.

11. Physiochemical properties
Most lipid soluble drugs cross biological membranes
Hydrophilic drugs do not readily cross membranes but go through slit junctions

12. Volume of Distribution (Vd)
Drugs with high Vd
Have higher concentrations in tissues than in plasma.
Relatively lipid soluble.
Distributed intracellularly
Not efficiently removed by haemodialysis.
e.g. phenytion, morphine, digoxin

13. Volume of Distribution (Vd)
Drugs with low Vd
confined to plasma & interstitial fluid.
distributed in extracellular compartments.
Polar comp or lipid insoluble drugs. e.g. Carbenicillin, vecuronium, gentamycin.
High MW e.g. heparin – insulin.
High plasma protein binding e.g. warfarin.
Do not cross BBB or placental barriers.

14. Capillary permeability
Endothelial cells of capillaries in tissues other than brain have wide slit junctions allowing easy movement & distribution.
Brain has tight junction Blood Brain Barrier (BBB).

15. Blood brain barrier (BBB):
Only lipid soluble drugs or carrier mediated transport can cross BBB.
Hydrophilic drugs (ionized or polar drugs) can not cross BBB.
Inflammation as in meningitis increase permeability to hydrophilic drugs
e.g. penicillin & gentamycin
Placental barrier
Lipid soluble drugs can cross placental barrier and enter the fetal blood.

20. Binding of Drugs
Plasma proteins binding.
Tissue proteins binding.

21. Plasma protein binding
Drugs can bind to plasma proteins (acidic drug bind to albumin while basic drugs bind to glycoprotein)
Drugs exist in two forms bound and unbound forms in equilibrium
Unbound drug (free) bound drug

22. Plasma protein binding and drug distrubution
Drug + Protein ⇄ Drug-Protein Complex
(Active, free) (Inactive, bound)
Competition between drugs for plasma protein-binding sites may increase the
"free fraction," possibly enhancing the effects of the drug displaced. Example:
sulfonamides and bilirubin in a neonate

23. Displacement
Competition for the same binding site on the plasma proteins may occur between two drugs  displacement of
one drug & increasing its concentrations & effects.
Aspirin + Albumin-warfarin 
Albumin-aspirin + free warfarin  bleeding.

25. Tissues Binding Drugs can bind to specific tissue
Tetracycline bind to bone
Iodides accumulate in salivary & thyroid glands

26. bound form of drug
non diffusible form
can not combine with
receptors
not available for
elimination
has long duration of
action (t ½).
Unbound form of drug
diffusible form
combine with receptors
available for elimination
has short duration of
action (t ½).

27. Characters & consequences of Binding
Usually reversible.
determines volume of distribution (vd)
Slows drug metabolism & excretion.
Prolongs duration of drug action (t1/2).
Result in clinically important drug interactions.

28. Redistribution
Redistribution of the drug away from its site of action to other tissues where it can not produce an action e.g. thiopental
Termination
Biotransformation.
Excretion.
Redistribution.

29. Bioavailability
Is the fraction of unchanged drug that enters systemic circulation after administration and becomes available to produce an action
I.V. provides 100% bioavailability i.e F= 1.
Subcutaneous, intramuscular, oral, rectal, and other extravascular routes of administration require that the drug be absorbed first, which can reduce bioavailability.
Bioavailability (F) = AUC oral
AUC IV

31. Absolute bioavailability
Absolute bioavailability: The bioavailability of a drug product is compared to its intravenous standard formulation.
complete concentration-time profiles are needed for both the intravenous and other routes of administration.

32. Relative bioavailability
Relative bioavailability: This calculation is determined when two products are compared to each other, not to an intravenous standard .
This is commonly calculated in the generic drug industry to determine that the generic formulation (e.g., a tablet) is bioequivalent to the original formulation (e.g., another tablet).
E.g Tylenol (paracetamol 500 mg) compared panadol (paracetamol 500 mg)

33. Relative bioavailability
is important to get an idea of how formulations or routes of administration differ
dosage adjustment when changing formulations or routes of administration.
Pharmaceutical industries conduct bioequivalence studies for their new product to decide on formulation for the clinical use.

34. Bioequivalence
Drug products are considered to be pharmaceutical equivalents if they contain the same active ingredients and are identical in strength or concentration, dosage form, and route of administration.
Two drug products are considered to be bioequivalent when the rates and extents of bioavailability of the active ingredient in the two products are not significantly different under suitable test conditions.

35. Molecular weight of drug. Drug Formulation (rate of dissolution).
Factors Affecting Bioavailability:
1. Drugs
Molecular weight of drug.
Drug Formulation (rate of dissolution).
(solution > suspension > capsule > tablet)
Drug solubility of the drug
Chemical instability in gastric pH
(Penicillin & insulin )

36. First pass metabolism First pass metabolism
For example, when the B–blocking agent propranolol is given intravenously, its bioavailibilty is 100% but
when it is given orally approximately
20% of the administered dose reaches the systemic circulation as intact drug due to first pass metabolism.

37. First pass metabolism

38. Greater blood flow increases bioavailability
Factors Affecting Bioavailability (BAV):
Blood flow to absorptive site
Greater blood flow increases bioavailability
Intestine has greater blood flow than stomach
Surface area available for absorption.
Intestinal microvilli increases it
Rate of gastric emptying
rapid gastric emptying fast transit to intestine
pH of gut

39. Diarrhea reduce absorption
Intestinal motility (Transit Time)
Diarrhea reduce absorption
Drug interactions
Food
slow gastric emptying
generally slow absorption