In addition to the lipid–water partition coefficient of drugs, local blood flow, and intestinal surface area, other factors may affect absorption from the gastrointestinal tract.
Gastric Emptying Time
The rate of gastric emptying markedly influences the rate at which drugs are absorbed, whether they are acids, bases, or neutral substances. In general, factors that accelerate gastric emptying time, thus permitting drugs to reach the large absorptive surface of the small intestine sooner, will increase drug absorption unless the drug is slow to dissolve.
Intestinal Motility
Increased gastrointestinal motility may facilitate drug absorption by thoroughly mixing intestinal contents and thereby bringing the drug into more intimate contact with the mucosal surface.
However, the opposite may also occur in that an increase in motility may reduce contact time in the upper portion of the intestine where most of drug absorption occurs. Conversely, a decrease in gastrointestinal motility may promote absorption by increasing contact time. Thus, the effect depends on the drug and change in motility. Serious intestinal diseases, particularly those associated with intestinal sloughing, can be expected to alter drug absorption dramatically.
Food
Absorption of most drugs from the gastrointestinal tract is reduced or delayed by the presence of food in the gut. Drugs such as the tetracyclines, which are highly ionized, can complex with Ca++ ions in membranes, food, or milk, leading to a reduction in their rate of absorption. For drugs that are ionized in the stomach and un-ionized in the intestine, overall absorption will be delayed by any factor that delays gastric emptying. Finally, increased splanchnic blood flow, as occurs during eating, will increase the rate of drug absorption.
Formulation Factors
The ability of solid drug forms to dissolve and the solubility of the individual drug in the highly acidic gastric juice must be considered. For example, although the anticoagulant dicumarol has a very high lipid– water partition coefficient, it precipitates at the low pH of gastric juice, and the rate of its absorption is thereby reduced. This may be overcome by covering the tablets with an enteric coating that dissolves only in the relatively alkaline secretions in the small intestine.
Drugs administered in aqueous solution are absorbed faster and more completely than tablet or
suspension forms. Suspensions of fine particles (microcrystalline) are better absorbed than are those of larger particles.
Metabolism and Efflux Transporters
Drugs may be inactivated in the gastrointestinal tract before they are absorbed. Until recently, only gut microflora were implicated in the metabolism of drugs in the gastrointestinal system, affecting drug absorption.
However, it has now become apparent that drug metabolizing enzymes, such as the cytochrome P450 enzymes, play a major role in determining the extent of drug absorption of some drugs. Significant expression of cytochrome P450 3A4 and 3A5 occurs in the enterocytes lining the small intestine. These drug-metabolizing enzymes are responsible for approximately 50% of the cytochrome P450–mediated drug metabolism (see Chapter 4) and thus can be expected to play a major role in the pre-systemic metabolism of a number of drugs.
Recently, it has also been discovered that efflux transporters (transporters that pump drug or substrate out of a cell) are also present in human intestinal enterocytes on the apical side nearest the lumen of the intestine. The predominant transporter protein identified to date is P glycoprotein (Pgp), which is a product of the MDR1 gene.
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