![]() It is not unreasonable to presume that one or more components of grapefruit juice degrade intestinal CYP3A4 enzyme by way of irreversible “suicide” inhibition. The mechanism of the decrease in CYP3A4 protein likely represents either accelerated protein degradation or reduced messenger RNA translation. The failure of messenger RNA expression to decrease with grapefruit juice would suggest that this process is not transcriptionally regulated. Moreover, this phenomenon was reproducible when human cell lines modified to express CYP3A4 were exposed to grapefruit juice. 4, 12 This effect was selective in that concentrations of CYP1A1 and CYP2D6 did not fall. The latter mechanism was first detected when it was observed that recurrent ingestion of grapefruit juice selectively decreased enterocyte expression (obtained by small bowel biopsy) of both CYP3A4 and CYP3A5, thereby increasing drug bioavailability. 11 Grapefruit juice appears to reduce CYP3A4 activity by both reversible (competitive or noncompetitive) and irreversible (mechanism-based or suicide inhibition) mechanisms as well as through a true loss of CYP3A4. ![]() The effect of some CYP3A4 inhibitors dissipates with repeated administration, because they produce a time-dependent induction of CYP3A4 via up-regulation of CYP3A messenger RNA and protein, which appears not to be the case with grapefruit juice. 4, 10 Action of Grapefruit Juice on Intestinal CYP Enzymes Third, in standard dose amounts, grapefruit juice has no effect on the pharmacokinetics of these medications when they are intravenously administered. An interaction involving hepatic CYP3A would be expected to influence drug half-life. 9 Second, grapefruit juice increases the area under the plasma concentration time curve, a calculable measure of whole-body medication exposure, with minimal if any change in drug half-life. ![]() Hepatic CYP3A is at best moderately affected by grapefruit juice administration and only with its chronic administration. Only the CYP3A isoforms localized to mucosal cells of the small intestine are inhibited by grapefruit juice. First, medications interacting with grapefruit juice typically are subject to metabolism by the enterocyte CYP3A4 enzyme system. Several findings point to grapefruit juice having a principal effect on the intestinal CYP system with a minor effect at the hepatic level. 4–8 The emphasis in this review will be on the interaction between grapefruit juice and calcium channel blockers (CCB). 3 This literature has been extensively reviewed, and the reader is directed to several of these reviews for additional information. 2 This singular observation has fueled a large volume of grapefruit juice–drug interaction research, with in excess of 225 publications involving more than 25 drugs appearing in the scientific literature. 1, 2 This interaction was discovered by coincidence in the course of an ethanol–drug interaction study in which grapefruit juice was used to mask the taste of the ethanol vehicle. This interaction substantially increased the systemic exposure to felodipine and by this amplified its pharmacodynamic effects. In 1989, it was noted that co-administration of the calcium antagonist felodipine with usual doses of commercially available grapefruit juice substantially decreased the pre-systemic clearance of felodipine. Visit the UPMC Heart and Vascular Institute or call 1-855-UPMC-HVI to learn more.Calcium channel blockers, grapefruit juice, felodipine, bergamottin, 6′, 7′-dihydroxybergamottin, flavanoids, furanocoumarins If you’re worried about getting enough vitamin C and potassium in your diet, a registered dietitian – an expert on diet and nutrition - can help you find other foods that are both healthy and safe based on the medicines you take. If grapefruit is a regular part of your diet, you might need to lower the amount that you eat, or avoid it altogether, depending on what medicines you take.
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