Major Active Components in Grapefruit, Orange, and Apple Juices Responsible for OATP2B1-Mediated Drug Interactions

Shirasaka, Yoshiyuki; Shichiri, Megumi; Mori, Takanori; Nakanishi, Takeo; Tamai, Ikumi

doi:10.1002/jps.23653

Cited by 61 publications

(28 citation statements)

References 32 publications

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“…These results are consistent with another in vivo report [12]. Furthermore, Shirasaka et al reported that naringin, a component in GFJ, is the predominant molecule responsible for the inhibition of OATP2B1, while phloridzin and phloretin are the primary components contributing to inhibition of OATP2B1-mediated uptake in AJ [15]. Naringin has also been reported to inhibit P-gp [35,36], and P-gp significantly contributes to the pharmacokinetics of fexofenadine enantiomers [24,25,37].…”

Section: Figsupporting

confidence: 87%

“…If this effect of GFJ could be attributed to inhibition of hepatic OATP-mediated transport, the plasma concentrations of both enantiomers would have been somewhat enhanced, as described previously [1e3]. In addition, recent studies have found that OATP2B1 is a major OATPtransporter in the small intestine and that the uptake/transport of fexofenadine in oocytes injected with OATP2B1 cRNA is significantly decreased in the presence of GFJ [15,33,34]. Therefore, these results suggested that GFJ inhibited the intestinal OATP2B1-mediated transport of fexofenadine enantiomers and may alter the pharmacokinetics of both enantiomers.…”

Section: Discussionmentioning

confidence: 73%

“…*** P < 0.001, between control phase and GFJ phase. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 the inhibitory effects of OATP2B1 [15]; the apparent half-maximal inhibitor concentrations (IC 50 ) were in the order of GFJ < orange juice (OJ) < AJ, and the inhibitory effect of GFJ was most potent. However, the present results indicated that the GFJ-dependent reductions in plasma concentrations of fexofenadine enantiomers were similar to or less than those induced by AJ and that the inhibitory effects of AJ were greater than those of GFJ.…”

Section: Figmentioning

confidence: 98%

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The change of pharmacokinetics of fexofenadine enantiomers through the single and simultaneous grapefruit juice ingestion

Akamine

Miura

Komori

et al. 2015

Drug Metabolism and Pharmacokinetics

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Section: Figsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 73%

Section: Figmentioning

confidence: 98%

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The change of pharmacokinetics of fexofenadine enantiomers through the single and simultaneous grapefruit juice ingestion

Akamine

Miura

Komori

et al. 2015

Drug Metabolism and Pharmacokinetics

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“…The IC 50 s recovered in the current work differed somewhat from those recovered using OATP2B1overexpressing Xenopus laevis oocytes [33]. For example, hesperidin showed no inhibition at the concentrations tested in MDCKII cells (current work), but was a potent inhibitor in oocytes (IC 50 , >300 vs. 1.92 μM).…”

Section: Discussionmentioning

confidence: 53%

Prioritizing pharmacokinetic drug interaction precipitants in natural products: application to OATP inhibitors in grapefruit juice

Johnson

Won

Köck

et al. 2017

Biopharm & Drug Disp

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Natural products, including botanical dietary supplements and exotic drinks, represent an ever-increasing share of the health care market. The parallel ever-increasing popularity of self-medicating with natural products increases the likelihood of co-consumption with conventional drugs, raising concerns for unwanted natural product-drug interactions. Assessing the drug interaction liability of natural products is challenging due to the complex and variable chemical composition inherent to these products, necessitating a streamlined preclinical testing approach to prioritize precipitant individual constituents for further investigation. Such an approach was evaluated in the current work to prioritize constituents in the model natural product, grapefruit juice, as inhibitors of intestinal organic anion-transporting peptide (OATP)-mediated uptake. Using OATP2B1-expressing MDCKII cells and the probe substrate estrone 3-sulfate, IC50s were determined for constituents representative of the flavanone (naringin, naringenin, hesperidin), furanocoumarin (bergamottin, 6′,7′-dihydroxybergamottin), and polymethoxyflavone (nobiletin and tangeretin) classes contained in grapefruit juice juice. Nobiletin was the most potent (IC50, 3.7 μM); 6′,7′-dihydroxybergamottin, naringin, naringenin, and tangeretin were moderately potent (IC50, 20–50 μM); and bergamottin and hesperidin were the least potent (IC50, >300 μM) OATP2B1 inhibitors. Intestinal absorption simulations based on physiochemical properties were used to determine ratios of unbound concentration to IC50 for each constituent within enterocytes and to prioritize in order of pre-defined cut-off values. This streamlined approach could be applied to other natural products that contain multiple precipitants of natural product-drug interactions.

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“…Naringenin is a potent inhibitor of organic anion transporting polypeptide (OATP), a compound whose inhibition may impair oral absorption of certain drugs, e.g. fexofenadine [ 11 ]. In the light of current knowledge, enantiomers of naringenin should be treated as Pleiotropic, Stereoselective Inhibitors of Cytochrome P450 Isoforms, in other words, as substances that may potentially affect the metabolism of many drugs [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

Does consumption of red grapefruit juice alter naringenin concentrations in milk produced by breastfeeding mothers?

et al. 2017

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The content of certain ingredients of human milk, such as flavonoids, depend on the types and amounts of plant products consumed and may vary from woman to woman. The aim of the study was to determine to what extent consumption of an average amount of grapefruit juice (250 ml) affected naringenin content in human milk. A total of 14 breastfeeding mothers were included in the study. The subjects remained on a diet with restricted intake of naringenin for a total of five days except on the third day, when they drank a single serving of 250 ml of grapefruit juice. A considerable subject-to-subject variability in naringenin content was observed in both initial and subsequent determinations. Baseline concentration values, which may reflect naringenin content in the milk produced by the breastfeeding mother who eat an everyday (unmodified) diet, ranged from 420.86 nmol/l to 1568.89 nmol/l, with a mean of 823.24 nmol/l. Switching to the modified diet resulted in a decrease in naringenin concentrations to the mean value of 673.89 nmol/l measured 48 hours after the switch. The highest mean values were observed four and 12 hours after consumption of the juice, equalling 908.25 nmol/l (SD ± 676.84 nmol/l) and 868.96 nmol/l (SD ± 665.54 nmol/l), respectively. Naringenin is commonly found in human milk in quantities expressed in nmol/l, and its concentrations vary from woman to woman. Consumption of 250 ml of red grapefruit juice by breastfeeding mothers does not significantly alter naringenin concentrations in their milk.

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Major Active Components in Grapefruit, Orange, and Apple Juices Responsible for OATP2B1-Mediated Drug Interactions

Cited by 61 publications

References 32 publications

The change of pharmacokinetics of fexofenadine enantiomers through the single and simultaneous grapefruit juice ingestion

The change of pharmacokinetics of fexofenadine enantiomers through the single and simultaneous grapefruit juice ingestion

Prioritizing pharmacokinetic drug interaction precipitants in natural products: application to OATP inhibitors in grapefruit juice

Does consumption of red grapefruit juice alter naringenin concentrations in milk produced by breastfeeding mothers?

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