Amounts and variation in grapefruit juice of the main components causing grapefruit–drug interaction

Fukuda, Katsuyuki; Guo, Lian‐Qing; Ohashi, Nobuyuki; Yoshikawa, Masayoshi; Yamazoe, Yasushi

doi:10.1016/s0378-4347(00)00104-3

Cited by 69 publications

(65 citation statements)

References 16 publications

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“…Later, bergamottin and 6',7'-dihydroxybergamottin, two of the major furanocoumarins in GFJ, were identified as mechanism-based inhibitors, as well as reversible inhibitors of CYP3A4 (Schmiedlin-Ren et al, 1997;He et al, 1998;Guo et al, 2000). These furanocoumarins were not detected in orange juice (OJ) or apple juice (AJ), which is consistent with reports showing no effect of OJ on intestinal absorption of CYP3A4 substrates (Bailey et al, 1991;He et al, 1998;Fukuda et al, 2000;Paine et al, 2006Paine et al, , 2008.…”

Section: Introductionsupporting

confidence: 90%

Long-Lasting Inhibitory Effect of Apple and Orange Juices, but Not Grapefruit Juice, on OATP2B1-Mediated Drug Absorption

et al. 2012

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Enzyme-based grapefruit juice (GFJ)-drug interactions are mainly due to mechanism-based irreversible inhibition of metabolizing enzyme CYP3A4 by GFJ components, but the transporter organic anion transporting polypeptide (OATP)2B1 is also a putative site of interaction between drugs and fruit juices (FJ) in the absorption process. Here we aimed to investigate the effect of preincubation with FJ on OATP2B1-mediated transport of drugs in vitro. When OATP2B1-expressing Xenopus oocytes were preincubated with GFJ, orange juice (OJ), or apple juice (AJ), AJ induced a remarkable decrease in OATP2B1-mediated estrone-3-sulfate uptake in a concentration-dependent manner (IC 50 = 1.5%). A similar but less potent effect was observed with OJ (IC 50 = 21%), whereas GFJ had no effect. Similar results were obtained in preincubation studies using fexofenadine. Preincubation with OJ and AJ resulted in timedependent inhibition of OATP2B1. Again, AJ had the more potent effect; its action lasted for at least 240 minutes, suggesting that AJ irreversibly inhibits OATP2B1-mediated drug uptake. Kinetic analysis revealed that coincubation and preincubation with AJ reduced OATP2B1-mediated estrone-3-sulfate uptake via competitive and noncompetitive mechanisms, respectively. Thus, OATP2B1 is functionally impaired through both competitive and long-lasting inhibition mechanisms by AJ and OJ, but not GFJ. Interestingly, although GFJ but not AJ is able to irreversibly inhibit CYP3A4, in the case of OATP2B1, AJ but not GFJ has a long-lasting inhibitory effect. Accordingly, complex FJ-drug interactions may occur in vivo, and their clinical significance should be examined.

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Section: Introductionsupporting

confidence: 90%

Long-Lasting Inhibitory Effect of Apple and Orange Juices, but Not Grapefruit Juice, on OATP2B1-Mediated Drug Absorption

et al. 2012

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“…In contrast to the acute effect of grapefruit juice, studies in rodents have shown that long-term grapefruit juice administration enhances nifedipine clearance and induces hepatic oxidative enzymes (Dakovic et al, 1999;Mohri et al, 2000). Although several hundred components have been identified in grapefruit juice (Ranganna et al, 1983;Fukuda et al, 1997Fukuda et al, , 2000, bergamottin and 6Ј,7Ј-dihydroxybergamottin are predominant components of grapefruit juice that are mechanism-based inactivators of CYP3A and major human liver microsomal P450s (Schmiedlin-Ren et al, 1997;He et al, 1998;Guo et al, 2000). In rats, administration of bergamottin in duodenum at doses equivalent to that in grapefruit juice resulted in increased AUC of nifedipine, an effect similar to grapefruit juice (Mohri and Uesawa, 2001).…”

mentioning

confidence: 99%

Effects of Bergamottin on Human and Monkey Drug-Metabolizing Enzymes in Primary Cultured Hepatocytes

Wen¹,

Sahi²,

Urda³

et al. 2002

Drug Metab Dispos

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ABSTRACT:We investigated the effect of bergamottin, a major furanocoumarin in grapefruit juice, on phase I and phase II drug-metabolizing enzymes using cultured human and monkey hepatocytes. Both cultured systems were compared and evaluated for the direct effects of bergamottin as well as control treatments on liver enzymes. Treatment of hepatocytes with 0.1, 1, 5, and 10 M bergamottin resulted in a concentration-dependent reduction in CYP3A4 activity (40-100%) in both human and monkey cells, as measured by testosterone 6␤-hydroxylase activity. Bergamottin was potent at eliciting these inhibitory effects at both basal and induced states of CYP3A. Bergamottin (5 M) completely inhibited ␣-naphthoflavone-induced ethoxyresorufin O-dealkylase (EROD) and methoxyresorufin O-dealkylase (MROD) activities in human hepatocytes and caused a 100% decrease in EROD activity in monkey hepatocytes. A 48-h exposure of cultured human hepatocytes to bergamottin resulted in increased levels of immunoreactive CYP3A4, CYP1A1, and CYP1A2 proteins, and CYP3A4, CYP1A1, CYP1A2, CYP2B6, and UDP-glucuronosyl transferase mRNAs. There was only a 20 to 30% reduction in glucuronidation and sulfation of 4-methylumbelliferone in human hepatocytes by 10 M bergamottin and no effect on conjugation in the monkey hepatocytes. These results suggest that bergamottin causes both inhibition of CYP3A and CYP1A1/2 enzymatic activities and induction of correspondent proteins and mRNAs.

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“…According to previous studies (Fukuda, Guo, Ohashi, Yoshikawa, & Yamazoe, 2000;Guo & Yamazoe, 2004;Manthey & Buslig, 2005;Ohta et al, 2002), the typical [MþH] þ ions of already identified furanocoumarins by ESI were at m/z 203, 339, 355, 373, 709 and 727. They correspond to bergaptol, bergamottin, 6 0 ,7 0 -epoxybergamottin and 6 0 ,7 0 -dihydroxybergamottin, paradisin B and paradisin A and C, respectively.…”

Section: Identification Of Furanocoumarinsmentioning

confidence: 82%

New furanocoumarins detected from grapefruit juice retentate

Buslig

Haun

et al. 2009

Natural Product Research

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Grapefruit (Citrus paradisi Macf.) furanocoumarins and related compounds have been shown to interact with the enterocyte cytochrome P450, CYP3A4, and as a result they affect the bioavailibility of certain drugs. Only a few grapefruit furanocoumarins have been identified so far. In this study, grapefruit juice retentate, rich in furanocoumarins, was extracted and then separated by flash chromatography for the examination of new compounds. Finally, nine new furanocoumarins were detected in different fractions according to their UV spectra and mass spectrometric properties by LC-MS (liquid chromatography mass spectrometry) and tentatively designated as FC 338, FC 420, FC 524, FC 530, FC 540, FC 546, FC 552, FC 570 and FC 614.

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Amounts and variation in grapefruit juice of the main components causing grapefruit–drug interaction

Cited by 69 publications

References 16 publications

Long-Lasting Inhibitory Effect of Apple and Orange Juices, but Not Grapefruit Juice, on OATP2B1-Mediated Drug Absorption

Long-Lasting Inhibitory Effect of Apple and Orange Juices, but Not Grapefruit Juice, on OATP2B1-Mediated Drug Absorption

Effects of Bergamottin on Human and Monkey Drug-Metabolizing Enzymes in Primary Cultured Hepatocytes

New furanocoumarins detected from grapefruit juice retentate

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