TABLE 3.1 Some Factors Influencing Gastric Emptying Time
Factor Increased gastric emptying rate Decreased gastric emptying rate
Physiological Liquids, gastric distention Solids, acids, fat
Pharmacological Reserpine, anticholinesterases, guanethidine, cholinergic Anticholinergic drugs, ganglionic blocking drugs, agents narcotic analgesics
Reprinted with permission from W. S. Nimmo. Drugs, disease and altered gastric emptying. Clin Pharmacokinet 1976;1:189.
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 (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 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 entero-cytes 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 presystemic metabolism of a number of drugs. For example, less than 20% of a dose of the im-munosuppressant cyclosporine reaches the systemic circulation 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 metabolism is the major factor responsible for the low percentage of an oral dose of cyclosporine reaching the systemic circulation. Cytochrome P450 2C9 and 2C19 are also expressed in measurable quantities in the human intestine. With any of these four cytochrome P450 enzymes, 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 intestine. 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 reaching the systemic circulation.
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