DRUG-INTERACTIONS WITH GRAPEFRUIT JUICE

Some drugs demonstrate a significantly greater (up to 3-fold) mean ora l bioavailability on coadministration with grapefruit juice. With some calcium antagonists, the benzodiazepines midazolam and triazolam and the antihistamine terfenadine, changes in bioavailability are accompan ied by altered drug action. Study design factors possibly contribute t o the magnitude of changes in drug bioavailability; they include the s ource of the citrus, its intake schedule, drug formulations and indivi dual metabolising capacity. The components of citrus juice that are re sponsible for clinical drug interactions have yet to be fully determin ed. Based on the flavonoid naringin's unique distribution in the plant kingdom, abundance in grapefruit and ability to inhibit metabolic enz ymes, naringin is likely to be one of the grapefruit components influe ncing drug metabolism. Other components present in citrus fruit, such as furanocoumarins, may be more potent inhibitors than flavonoids and are under investigation. Conclusions drawn from clinical drug interact ion studies should be considered specific to the citrus fruit products evaluated because of the variation in their natural product content. The predominant mechanism for enhanced bioavailability is presumably t he inhibition of oxidative drug metabolism in the small intestine. The consistent findings across studies of diverse cytochrome P450 (CYP) 3 A substrates support the mechanistic hypothesis that 1 or more grapefr uit juice components inhibit CYP3A enzymes in the gastrointestinal tra ct. The evaluation of the need to avoid the concomitant intake of grap efruit products with drugs is best done on an individual drug basis ra ther than collectively by drug class. Based on the narrow therapeutic range of cyclosporin and research experience in organ transplant recip ients, its interaction with grapefruit juice is likely to be clinicall y significant.