Pharmacokinetics Drug Distribution and Drug Reservoirs Course Coordinator

Pharmacokinetics: Drug Distribution and Drug Reservoirs Course Coordinator Jamaluddin Shaikh, Ph. D. School of Pharmacy, University of Nizwa Lecture-7 October 03, 2011

Pharmacokinetic Components

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

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

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

Brain Capillaries

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. This maintains the free-drug concentration as a constant fraction of the total drug in the plasma Free Drug Bound Drug SYSTEMIC CIRCULATION BIOTRANSFORMATION EXCRETION TISSUE RESERVOIRS Free Bound

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

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

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) • Drugs can bind with varying affinities • Albumin has the strongest affinities for anionic drugs (weak acids) and hydrophobic drugs. Most hydrophilic drugs and neutral drugs do not bind to albumin

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, and the bounddrug fraction is high • 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

Competition for Binding Between Drugs

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

Cellular 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 • The major one is synovial fluid in the joints, saliva, tears