Grapefruits and drugs: when is statistically significant clinically significant?

Editorial Lown et al. (1) report a significant advance in describing a new mechanism by which ingested nutrients may change exposure to drug therapy. Grapefruit juice was reported to increase plasma concentrations of felodipine and nifedipine when the drug was concurrently administered with grapefruit juice (2). The potential clinical importance of such an interaction was noted when cyclosporine A (3) and terfenadine (4) were noted to have decreased oral clearance with concomitant grapefruit juice ingestion. Due to the relatively narrow therapeutic index of each of these drugs, some have expressed concern and the wish to highlight grapefruit juice as a source of risk for some patients. This point of view warrants some discussion. The mechanism by which grapefruit juice decreases oral clearance of certain drugs is via decreased activity of intestinal cytochrome P-450, specifically the CYP3A isoforms (5). However until the report in this issue of the Journal , this had been based on inference from the findings that all drug substrates with oral clearance decreased by grapefruit juice were also CYP3A substrates. Similarly, until the present report, mecha-nistic studies were oriented toward identification of chemi-cal(s) in grapefruit juice which inhibited CYP3A activity by direct binding to the enzyme. The expected result was that when the appropriate chemical(s) were identified, competitive or noncompetitive inhibition of the enzyme(s) would be demonstrated. Specific components of grapefruit juice which have been studied for CYP3A inhibition include quercetin (6), nar-ingin and naringenin (7), and 6 Ј ,7 Ј-dihydroxybergamottin (8). Although the current report does not exclude substances in grapefruit juice which directly inhibit the CYP3A enzyme catalytic activity, it rather conclusively demonstrates that an important component of grapefruit juice–mediated decrease in oral clearance of CYP3A drug substrates is a posttranscrip-tional decrease in the amount of small intestinal CYP3A enzyme. Of course the next step is identification of the mechanism of decreased immunoreactive protein product in the face of unchanged CYP3A4 mRNA. To do this the grapefruit juice component(s) must first be identified, however the task is substantially more complex than simply screening for CYP3A in-hibitors. The authors postulate the presence of a mechanism-based, or " suicide " inhibitor of small intestinal CYP3A. A well-described example of such a mechanism is inactivation of specific phenobarbital-inducible hepatic cytochrome P-450 isozymes by chloramphenicol (9). In this instance chloram-phenicol is covalently bound as an oxamic acid adduct to an epsilon amino group of a lysine residue of the …