1. Pharmacokinetics: Drug Distribution and Drug Reservoirs
Course Coordinator
Jamaluddin Shaikh, Ph.D.
School of Pharmacy, University of Nizwa
Lecture-7
February 25, 2012

2. Pharmacokinetic Components

3. Mechanism of Drug Distribution
A process by which a drug reversibly leaves the bloodstream and enters the extracellular fluid and/or the cells of the tissues
Mechanism of Drug Distribution
First phase of distribution:
Compose of cardiac output and regional blood flow
Involvement of heart, liver, kidney, brain
Steady state achieve after first few minutes of absorption
Second phase of distribution:
Delivery of drug to muscle, skin and fat
Steady state achieve after several minutes to hours of absorption

4. Factors Influencing Drug Distribution
Blood flow
Capillary permeability
Binding of the drug to plasma and tissue proteins
Relative hydrophobicity of the drug
Blood Flow
The rate of blood flow to the tissue capillaries varies widely as a result of the unequal distribution of cardiac output to the various organs
Blood flow to the brain, liver, and kidney is greater than that to the skeletal muscles; adipose tissue has a lower rate of blood flow

5. Capillary Permeability
Capillary structure:
Capillary structure varies widely in
terms of the fraction drug distribution
Blood-brain barrier:
To enter the brain, drugs must pass through the endothelial cells of the capillaries of the CNS or be actively transported
Drug structure:
The chemical nature of a drug strongly influences its ability to cross cell membranes. Hydrophobic drugs readily move across most biologic membranes. By contrast, hydrophilic drugs do not readily penetrate cell membranes, and must go through the slit junctions

6. Brain Capillaries

7. Binding of Drugs to Plasma and Tissue Proteins
Reversible binding to plasma proteins sequesters drugs in a nondiffusible form
Plasma albumin is the major drug-binding protein and may act as a drug reservoir; i.e., as the concentration of free drug decreases due to elimination by metabolism or excretion, the bound drug dissociates from the protein.
Free Drug
EXCRETION
TISSUE
RESERVOIRS
Bound Drug
SYSTEMIC
CIRCULATION
Free
Bound
BIOTRANSFORMATION

8. Drug Reservoir Storage site of drugs in the body
Drugs at storage sites are pharmacologically not active
Three different storage systems:
Plasma proteins
Cellular reservoir
Transcellular reservoir

9. Binding of Drugs at Plasma proteins
Drug molecules may bind to plasma proteins, usually albumin
Bound drugs are pharmacologically inactive; only the free, unbound drug can act on target sites in the tissues, elicit a biologic response
Drug reservoir may depend on:
Binding capacity of albumin
Competition for binding between drugs

10. Binding Capacity of Albumin
The binding of drugs to albumin is reversible and may show low capacity (one drug molecule per albumin molecule) or high capacity (a number of drug molecules binding to a single albumin molecule)
Albumin has the strongest affinities for anionic drugs (weak acids) and hydrophobic drugs. Most hydrophilic drugs and neutral drugs do not bind to albumin

11. Competition for Binding Between Drugs
When two drugs are given, each with high affinity for albumin, they compete for the available binding sites. These drugs may divided into two classes
Class I drugs
If the dose of drug is less than the binding capacity of albumin, then the dose/capacity ratio is low. The binding sites are in excess of the available drug
Class II drugs
These drugs are given in doses that greatly exceed the number of albumin binding sites. The dose/capacity ratio is high, and a relatively high proportion of the drug exists in the free state, not bound to albumin

12. Competition for Binding Between Drugs

13. Clinical Importance of Drug Displacement
This is important when a patient taking a Class I drug, such as warfarin, is given a Class II drug, such as a sulfonamide antibiotic
Warfarin is highly bound to albumin, and only a small fraction is free, i.e., most of the drug is sequestered on albumin and is pharmacologically inactive
If a sulfonamide is administered, it displaces warfarin from albumin, and increases in the concentration of free warfarin in plasma

14. Trancellular Reservoirs
Many drugs accumulate in muscle and other cells in higher concentration than in the extracellular fluid
If the intracellular concentration is high and if the binding is reversible, the tissue involved may represent a suitable drug reservoir
Example, during long-term administration of antimalarial agent quinacrine, the concentration of drug in liver is several thousand times that in the plasma
Trancellular Reservoirs
Drug also cross epithelial cells and may accumulate in the transcellular fluids
Major one is synovial fluid in the joints, saliva, tears