FACTORS AFFECTING RATE OF GASTROINTESTINAL ABSORPTION
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.
The rate of gastric emptying markedly influences the rate at which drugs are absorbed, whether they are acids, bases, or neutral substances. In general, fac-tors that accelerate gastric emptying time, thus permit-ting drugs to reach the large absorptive surface of the small intestine sooner, will increase drug absorption unless the drug is slow to dissolve. A list of physiolog-ical, pathological, and pharmacological factors that in- fluence the rate of gastric emptying is provided in Table 3.1.
Increased gastrointestinal motility may facilitate drug absorption by thoroughly mixing intestinal contents and thereby bringing the drug into more intimate con-tact with the mucosal surface. However, the opposite may also occur in that an increase in motility may re-duce contact time in the upper portion of the intestine where most of drug absorption occurs. Conversely, a decrease in gastrointestinal motility may promote ab-sorption by increasing contact time. Thus, the effect de-pends on the drug and change in motility. Serious in-testinal diseases, particularly those associated with intestinal sloughing, can be expected to alter drug ab-sorption dramatically.
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 mem-branes, 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 ab-sorption will be delayed by any factor that delays gas-tric emptying. Finally, increased splanchnic blood flow, as occurs during eating, will increase the rate of drug absorption.
The ability of solid drug forms to dissolve and the sol-ubility of the individual drug in the highly acidic gas-tric 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 intes-tine. Drugs administered in aqueous solution are absorbed faster and more completely than tablet or suspension forms. Suspensions of fine particles (mi-crocrystalline) are better absorbed than are those of larger particles.
Drugs may be inactivated in the gastrointestinal tract before they are absorbed. Until recently, only gut mi-croflora 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 en-zymes, 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 entero-cytes lining the small intestine. These drug-metabolizing enzymes are responsible for approximately 50% of the cytochrome P450–mediated drug metabolism and thus can be expected to play a major role in the presystemic metabolism of a number of drugs. For example, less than 20% of a dose of the im-munosuppressant cyclosporine reaches the systemic cir-culation intact. In fact, most of the metabolism of cy-closporine prior to reaching the systemic circulation takes place in the gut via cytochrome P450 3A4 and 3A5, not in the liver, as might be expected. Thus, gut me-tabolism is the major factor responsible for the low per-centage of an oral dose of cyclosporine reaching the sys-temic circulation. Cytochrome P450 2C9 and 2C19 are also expressed in measurable quantities in the human intestine. With any of these four cytochrome P450 en-zymes, the variation in expression between individuals is substantial, and so their relative contribution to presystemic metabolism of drugs will vary from person to person.
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 ente-rocytes on the apical side nearest the lumen of the in-testine. The predominant transporter protein identified to date is P glycoprotein (Pgp), which is a product of the MDR1 gene. This transporter was originally identified as being overexpressed in tumor cells and responsible in part for multidrug resistance because of its role in the efflux of drugs out of tumor cells; thus the name mul-tidrug resistance (MDR) gene. It has become apparent that many of the drugs that are substrates for cy-tochrome P450 3A4 are also substrates for Pgp. As a substrate for Pgp, a drug will enter the cell, usually via passive diffusion, but then be picked up by the Pgp transporter and carried back to the gut lumen (efflux). As this continually occurs along the intestine, some of the drug molecules are prevented from being absorbed, which decreases overall absorption. Taken together, the Pgp transporter and the cytochrome P450 enzymes form a mechanism to reduce the amount of drug reach-ing the systemic circulation.