Saturday, April 09, 2005

DRUG INPUT AND DISPOSITION

This article has been published by the International Biopharmaceutical Association www.ibpassociation.org

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Drugs are compounds almost always foreign to the body. As such, they are not continually being formed and eliminated as are endogenous substances. The processes of inputting, distributing, and eliminating drugs are therefore of paramount importance in determining the onset, duration, and intensity of effect.
DRUG ABSORPTION
The process of drug movement from the site of administration toward the systemic circulation.
Drug product: The actual dosage form of a drug, consisting of the drug itself plus other ingredients formulated into a usable medicine; eg, as a tablet, capsule, or solution. Drug products are formulated for administration by a variety of routes, including oral, buccal, sublingual, rectal, parenteral, topical, and inhalational. The physicochemical properties of drugs, their formulations, and the routes of administration are important in absorption. A prerequisite to absorption of any drug is that it be able to enter into solution. The solid drug product (eg, tablet) must undergo disintegration and deaggregation, and the active ingredients must undergo dissolution before the drug can be absorbed.
Except when given IV (intravenously), a drug must traverse several semipermeable cell membranes before reaching the general circulation. These membranes act as biologic barriers that selectively inhibit the passage of drug molecules. Cell membranes are composed primarily of a bimolecular lipid matrix, containing mostly cholesterol and phospholipids, in which are embedded globular protein macromolecules of random size and composition. The membrane proteins may be involved in transport processes and may also function as receptors for cellular regulatory mechanisms. Membrane lipid provides stability to the membrane and determines its permeability characteristics.

Processes
The processes by which drugs move across a biologic barrier include passive diffusion, facilitated diffusion, active transport, and pinocytosis.
Passive diffusion: Transport across a cell membrane in which the driving force for movement is the concentration gradient of the solute. Most drug molecules are transported across a membrane by simple diffusion from a high concentration area (GI fluids) to a low concentration area (blood) without expenditure of energy. The net rate of diffusion is directly proportional to this net gradient and depends upon lipid solubility, degree of ionization, molecular size, and the area of the absorptive surface. Since the drug is rapidly removed by the systemic circulation and distributed into a large volume, the concentration of drug in blood is initially low compared with that at the site of administration. The resulting large concentration gradient serves as the driving force for absorption. However, since the cell membrane is lipoidal in nature, drugs that are lipid soluble diffuse more rapidly than drugs that are relatively lipid insoluble. Furthermore, small molecules tend to penetrate membranes more rapidly than do large ones.
Most drugs exist as weak organic acids or bases in both nonionized and ionized forms in an aqueous environment. The nonionized fraction is usually lipid soluble and diffuses readily across cell membranes. The ionized form cannot penetrate the cell membrane easily because of its low lipid solubility.
Facilitated diffusion: For certain molecules (glucose), the rates of penetration are greater than expected from their low lipid solubility and the concentration gradients present. It is postulated that a "carrier component" combines reversibly with the substrate molecule at the cell membrane exterior and that the carrier-substrate complex diffuses rapidly across the membrane with release of the substrate at the interior surface. This carrier-mediated diffusion process is characterized by selectivity and saturability. The carrier mechanism accepts for transport only those substrates having a relatively specific molecular configuration, and the process is limited by the availability of carrier. No expenditure of energy is required by this process; substrate is not transported against a concentration gradient.
Active transport: In addition to selectivity and saturability, active transport requires energy expenditure by the cell, and substrates may accumulate intracellularly against a concentration gradient. Active transport processes appear to be limited to agents with structural similarities to normal body constituents. These agents are usually absorbed from specific sites in the small intestine. Active transport processes have been identified for various ions, vitamins, sugars, and amino acids.
Pinocytosis refers to the engulfing of particles or fluid by a cell. The cell membrane invaginates (forms and opening), encloses the particle or solute, and then fuses again, forming a vesicle that later buds off within the interior of the cell. This mechanism also requires the expenditure of energy. Pinocytosis probably plays a minor role in drug transport.
Oral Administration
Because the oral route of administration is the most common, absorption usually refers to the transport of drugs across the membranes of the epithelial cells within the GI tract. Absorption after oral administration is confounded by differences down the alimentary canal in the luminal pH; surface area per luminal volume; perfusion of the tissue, bile, and mucus flow; and the epithelial membranes. The faster absorption of acids in the intestine compared with the stomach appears to contradict the hypothesis that the nonionized form of a drug more readily crosses membranes.
Gastric emptying and intestinal transit time: Because the absorption of virtually all compounds is faster from the small intestine than from the stomach, the rate of gastric emptying is a controlling step. Food, especially fatty foods, slows gastric emptying, which explains why some drugs are recommended to be taken on an empty stomach when a rapid onset of action is desired. The extent of absorption may be enhanced by food if the drug is poorly soluble (e.g., griseofulvin) or reduced if degraded in the stomach (e.g., penicillin G). Drugs that affect gastric emptying (parasympatholytic agents) also affect the rate of absorption of other drugs.
Parenteral Administration
Direct placement of a drug into the bloodstream (usually IV) ensures complete delivery of the dose to the general circulation. However, administration by a route that requires drug transfer through one or more biologic membranes to reach the bloodstream precludes a guarantee that all of the drug will eventually be absorbed. Intra-muscular (IM) or Sub-cutaneous (S.C.). injection of drugs bypasses the skin barrier, but the drug must penetrate the capillary walls. Because the capillaries tend to be highly porous, the perfusion (blood flow/gram of tissue) is a major factor in the rate of absorption. Thus, the injection site can markedly influence a drug's absorption rate.
Controlled-Release Dosage Forms
Controlled-release dosage forms are designed to reduce the frequency of dosing and to maintain more uniform plasma drug concentrations, thus providing a more uniform pharmacologic effect. Reduction of the absorption rate can be achieved in various ways: by coating the drug particles with wax or related water-insoluble material, by embedding the drug in a matrix from which it is released slowly during transit through the GI tract, or by complexing the drug with ion-exchange resins.
Topical controlled-release dosage forms have been designed to provide drug release for extended periods; eg, clonidine diffusion through a membrane provides controlled drug delivery over a period of 1 wk, and nitroglycerin-impregnated polymer bonded to an adhesive bandage provides controlled drug delivery over a period of 24 h. Drugs for transdermal delivery must have suitable skin penetration characteristics and high potency.

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