12 Ingestion of grapefruit juice reduces enteric CYP3A4 levels similarly in all subjects irrespective of the tissue CYP3A4 concentrations before ingestion. 17 Higher concentrations of CYP3A4 in the intestine, as logic would suggest, correlate with greater first-pass metabolism and lower attainable drug levels for felodipine. The expression of the CYP3A4 enzyme shows striking interindividual variability in both the liver and intestine with as much as an eightfold difference found in its intestinal content. 16 Interindividual Variability in the Effect of Grapefruit Juice 15 Such a recovery pattern is consistent with the time sequence of enzyme regeneration after irreversible (mechanism-based) inhibition. 13, 14 Complete recovery from the grapefruit juice effect may take up to 72 h after the last exposure with a recovery half-life from enteric CYP3A4 inhibition of approximately 24 h. For example, upon ingestion of grapefruit juice intestinal CYP3A4 concentration is reduced by 47% within 4 h, and the bioavailability-enhancing effect of ingested grapefruit juice is sustained for at least 24 h. 4 Such a hypothesis explains the rapid and sustained onset of CYP3A4 inhibition upon exposure to grapefruit juice. 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. Calcium channel blockers, grapefruit juice, felodipine, bergamottin, 6′, 7′-dihydroxybergamottin, flavanoids, furanocoumarins
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