Basic Principle of Pharmacokinetik

Dept. Pharmacology & Therapeutic

School of Medicine Universitas Sumatera Utara

Content
Defenition The movement of Drugs in the body : 1. Permeation : a. Aqueous diffusion b. Lipid diffusion c. Transport by special carrier d. Endocytosis/pinocytosis 2. Ficks Law of Diffusion 3. water & lipid solubility of drugs: a. Aqueous diffusion b. Lipid diffusion c. Ionization of weak acids and bases 4. Hands-Hasselbach relationship

Defenition

Pharmacokinetic
The actions of the body on the drug, including absorption, distribution, metabolism, and excretion. Elimination of a drug may be achieved by metabolism or by excretion. Biodisposition is a term sometimes used to describe the processes of metabolism and excretion.

Pharmacokinetic Principle
In practical therapeutics, a drug should be able to reach its intended site of action after administration by some convenient route In some cases, a chemical that is readily absorbed and distributed is administered and then converted to the active drug by biologic processes inside the body PRODRUG

Most often, a drug is administered into one body compartment, eg, the gut, and must move to its site of action in another compartment, eg, the brain Requires that the drug be absorbed into the blood from its site of administration and distributed to its site of action, permeating through the various barriers that separate these compartments A drug given orally to produce an effect in the central nervous system, these barriers include the tissues that comprise the wall of the intestine, the wall of the capillaries that perfuse the gut and the bloodbrain barrier, the walls of the capillaries that perfuse the brain Finally, after bringing about its effect, a drug should be eliminated at a reasonable rate by metabolic inactivation, by excretion from the body, or by a combination of these processes

Physiologic Barriers
A drug must overcome physical, chemical, and biological barriers to reach its molecular and cellular sites of action Most drugs must distribute from the blood stream into local tissues, a process that may be impeded by such stuctures as the blood brain barrier. Drug distribution occurs mainly through passive diffusion, the rate of which is affected by local ionic and cellular conditions

Drug Absorption, Distribution, Metabolism, and Exretion

Receptors Free Bound Tissue reservoirs Free Bound

Systemic circulation

Absorption
Protein bound drug

Free drug
Metabolites (active and inactive)

Excretion

Metabolism The basic principle of pharmacokinetic affect the amount of free drug that ultimately reaches the target site To elicit an effect on its target, a drug must be absorbed and then distributed to its target before being metabolized and excreted Free drug in the systemic circulation is in equilibrium with tissue reservoir, plasma proteins, and the target site (which usually consists of receptors); only the fraction of drug that succcessfully binds to specific receptors will have a pharmacologic effect

Metabolism of drug can result in both inactive and active metabolits

Permeation
The movement of drug molecules into and within the biologic environment. Four primary mechanism : 1. Aqueous diffusion 2. Lipid diffusion 3. Transport by special carriers 4. Endocytosis, pinocytosis Passive diffusion in aqueous or lipid medium is common, but active processes play a role in the movement of many drugs, especially those whose molecules are too large to diffuse readily

Drug Transport Mechanisms

Aqueous diffusion
The movement of molecules through the watery extracellular and intracellular spaces The membranes of most capillaries have small waterfilled pores that permit the aqueous diffusion of molecules up to the size of small proteins between the blood and the extravascular space. Aqueous diffusion of drug molecules is usually driven by the concentration gradient of the permeating drug, a downhill movement Passive process governed by Ficks law. Drug molecules that are bound to large plasma protein (eg. Albumin) will not permeate these aqueous pores

Lipid diffusion
The movement of molecules through membranes and other lipid structures The most important limiting factor for drug permeation, because of the large number of lipid barriers that separate the compartment of the body Passive process governed by Ficks law The lipid : aqueous partition coeffitient of a drug determines how readily the molecules moves between aqueous and lipid media In the case of weak acids and weak bases, the ability to move from aqueous to lipid varies with the pH of the medium The ratio of lipid soluble form to water-soluble form for a weak acid or weak base is expressed by the Henderson-Hasselbach

Transport by special carriers

Exist for certain substances that are important for cell function and too large or too insoluble in lipid to diffuse passively through membrane, eg, peptides, amino acids, glucose Saturable and inhibitable The carriers bring about movement by active transport or facilitated diffusion Not governed by Ficks law Selective inhibitors for these carrier probenecid, which inhibits transport of uric acid, penicillin, and other weak acids, is used to increase the excretion of uric acid in gout The family of P-glycoprotein transport molecule responsible for expulsion of certain drugs into the intestinal lumen

Transport by special carriers

Facilitated diffusion

Endocytosis, pinocytosis
Endocytosis : - the cell membrane involutes around the molecule to form a closed cavity or vesicle from which the drug is subsequently released into the interior of the cell - permits very large or very lipid insoluble chemicals to enter cells - B12 with intrinsic factor and iron with transferrin, and the complexes enter cells by this mechanism - Spesific receptors for the transport proteins must be present

Endocytosis, exocytosis
Exocytosis : - the reverse process, ie, the expulsion of membraneencapsulated material from cells. - responsible for the secretion of many substances from cells - examples : - many neurotransmitter substances are stored in membrane-bound vesicles in nerve endings to protect them from metabolic destruction in the cytoplasm - appropriate activation of the nerve ending causes fusion of the storage vesicle with the cell membrane and expulsion of its contens into the extracellular space