the overall Fsystemic is 0-25 (i.e., 25% of the dose reaches the systemic circulation). The absorption process can be broken down further into its component parts.

The fractions of the dose of drug that escape metabolism in the gut fluid, gut wall, and gut flora are /gut fluid, fgut wall, and fgut flora, respectively. In the above example, an fabsorbed of 0.5 represents the product of the three processes that affect absorption. It is often common to express the fraction surviving a specific process as 1 - ER (extraction ratio) for that process. Thus, the above relationship may be written as,

A change in the ER value for any of the above processes will have an effect on the systemically available dose of the orally administered drug.

An especially interesting and extensively researched drug-food (or drug-nutrient) interaction is that between grapefruit juice (as well as other fruit juices) and certain drugs, especially those with a high metabolic clearance that undergo substantial presystemic (first-pass) metabolism. The discovery of this interaction is an excellent example of serendipity and an illustration of Pasteur's famous statement, "In the field of experimentation, chance favors only the prepared mind." In their original study (136), the experimenters were attempting to examine the influence of ethanol on the pharmacokinetics of coadministered drugs. The ethanol was mixed (serendipitously) with grapefruit juice to mask the taste of the ethanol. A substantial interaction was noted with felodipine, an approximate threefold increase in bioavailability. Since that initial observation, numerous studies have indicated that many other drugs with diverse chemical structures having a high metabolic clearance participate in this interaction with grapefruit juice (not ethanol!). Many studies have been devoted to determining the mechanism(s) of this interaction, and the readers are referred to a recent symposium and book chapter that cover this topic (137,138). While we have a better understanding of the nature of the interaction, it now appears that there may be several processes going on.

The drugs that undergo this interaction are substrates for one of the major drug-metabolizing isozymes in the body, cytochrome P450 3A4 (CYP3A4). This enzyme has been referred to as being promiscuous (in a biochemical sense) in that it will accommodate and metabolize a very wide range of drug molecules, most of which are lipid soluble. Since this isozyme is responsible for the metabolism of many drugs, it is also involved in many drug-drug and, in this case, nutrient-drug interactions. This enzyme and many other isozymes are present in the mucosal surface cells (enterocytes) of the GIT. Therefore, the gut surface represents a potential site for drug metabolism. Phytochemicals present in grapefruit juice (furanocoumarins) are able to inhibit the CYP3A4 enzyme, resulting in less than usual presystemic GI metabolism of the drug (139). Since more of the dose of drug survives this metabolic step, there is a greater oral bioavailability of the drug. Enzyme inhibition could also be expressed in liver enzyme activity (resulting in increased bioavailability); however, liver enzymes appear to play a less significant role in this interaction than those in the GIT. The latter, however, may be more or less true depending upon the drug whose interaction is under investigation. For example, in the metabolic interaction between saquinavir and midazolam, saquinavir more than doubled the systemic oral bioavailability (Fsystemic) of midazolam (0.41-0.90). It was determined that the hepatic ER decreased from 0.39 to 0.17; however, the GIT ER decreased from 0.33 to 0 (50). The latter change had the greatest impact on the increased

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