DIET/NUTRIENT INTERACTIONS WITH DRUG TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 672

reductions in AUC and plasma concentration of cyclosporine, an immunosuppres-
sant, were observed in renal transplant patients after prolonged administration of
St. John's wort. 60 , 61 It was suggested in several case studies that the decreased cy-
closporine concentration during treatment with St. John's wort was the possible cause
of acute heart and kidney transplant rejection. 62 , 63 A similar pharmacokinetic in-
teraction was observed between St. John's wort and another immunosuppressant,
tacrolimus. Coadministration of St. John's wort (3 300 mg/day for 18 days) to 10

healthy volunteers significantly decreased tacrolimus AUC and increased its apparent
oral clearance. 64 Since indinavir, cyclosporine, and tacrolimus are dual substrates for
both Pgp and CYP3A4, it is likely that these interactions might involve induction of
Pgp or CYP3A4, or both. 44 , 64 , 65

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Grapefruit Juice The interaction of grapefruit juice with some drugs was discov-
ered accidentally when grapefruit juice was used to mask the taste of ethanol in a
study using the calcium channel blocker felodipine. Coadministration of grapefruit
juice increased the bioavailability of felodipine threefold. 66 Since then, a number
of studies have shown that grapefruit juice can enhance the bioavailability of many
clinically important drugs. 67 The predominant mechanism for grapefruit juice-drug
interactions appears to be the inhibition of CYP3A4 in the small intestine, resulting
in reduced presystemic metabolism and enhanced drug oral bioavailability. 68 An-
other important mechanism of grapefruit juice-drug interactions, as revealed in many
recent studies, is through the modulation of drug transporters, especially Pgp and
OATP. 25 , 69 − 75

Effects on Drug Transporters The major constituents in grapefruit juice include
flavonoids (e.g., naringin, naringenin, quercetin, kaempferol) and furanocoumarins
(e.g., bergamottin, 6 ,7 -dihydroxybergamottin). Many studies have shown that both
grapefruit juice and its major constituents can modulate the activities of several drug
transporters.
An early report of the grapefruit juice-drug interaction indicated that grapefruit
juice activated the transport of several Pgp substrates across MDCK-MDR1 cells. 76
However, the majority of the more recent studies have indicated that grapefruit juice
has an inhibitory effect on Pgp-mediated transport. In Caco-2 cells using talinolol and
digoxin as specific, yet metabolically stable Pgp substrates, the apical-to-basolateral
(absorptive) transport of talinolol and digoxin was increased significantly. 72 , 74 Sim-
ilarly, in Caco-2 cells and a rat everted sac model, grapefruit juice extracts or some
major components such as naringin and 6 ,7 -dihydroxybergamottin decreased sig-
nificantly the efflux or increased intracellular accumulation of several Pgp substrates,
such as rhodamine 123, fexofenadine, and saquinavir. 73 , 75 , 77 , 78 Using vinblastine as
a Pgp substrate, a number of studies indicated that several extracts of grapefruit juice
inhibited the activity of Pgp in Caco-2 cells with different potency. The ethyl ac-
etate extracts of grapefruit juice, followed by diethyl ethyl and methylene chloride
extracts, exhibited the greatest potency in increasing the permeability coefficient of
the apical-to-basolateral transport of vinblastine. 71 , 79