Journal of Chromatography B: Biomedical Sciences and Applications
Amounts and variation in grapefruit juice of the main components causing grapefruit–drug interaction
Introduction
Grapefruit juice has been shown to elevate the pharmacological efficacy of orally administered drugs, such as felodipine [1], cyclosporin [2], terfenadine [3], midazolam [4] and lovastatin [5], and sometimes evoke side reactions through yielding conditions with the extraordinary high plasma concentration. Bioavailability of these drugs after oral administration are increased 1.5 to 15-fold by the ingestion of grapefruit juice. Data compiled on this drug interaction suggest several essential properties of drug influenced: All the drugs are lipophilic and require the extensive oxidative biotransformation prior to the excretion. In addition, human studies in vitro [6], [7] and in vivo [8], [9] indicate the major role of CYP3A4 on the oxidative metabolisms. These lines of evidence suggest the involvement of specific grapefruit juice component on the first pass metabolism of drugs which is mediated by intestinal CYP3A4.
Flavonoid components, particularly naringin, are contained abundantly in this juice, as the major bitter principle [10], and thus their inhibitory properties were examined. Naringenin, an aglycone generated by hydrolysis of naringin in intestine [11], inhibit felodipine metabolism in vitro [6], [7]. However, naringin is shown to produce a negligible interaction with felodipine in vivo despite being given at a similar amount as that found in the grapefruit juice [12]. Consistent with the result, the inhibitory effect of ethyl acetate-extracts of grapefruit juice on microsomal CYP3A4 activity was not accounted for by the amounts of naringenin in the juice in our previous study [13]. To identify the component responsible for the inhibition of CYP3A4 activity, we examined the inhibitory effect of the extract by fractionation to isolate its inhibitory components. As the results, two new chemicals showing extremely high affinities for a form of cytochrome P450 (CYP3A4) were identified as 4-[[6-hydroxy-7-[[1-[(1-hydroxy-1-methyl)ethyl]-4-methyl-6-(7-oxo-7H-furo[3,2-g][1]benzopyran-4-yl)-4-hexenyl]oxy]-3,7-dimethyl-2-octenyl]oxy]-7H-furo[3,2-g][1]benzopyran-7-one (GF-I-1) and 4-[[6-hydroxy-7-[[4-methyl-1-(1-methylethenyl)-6-(7-oxo-7H-furo[3,2-g][1]benzopyran-4-yl)-4-hexenyl]oxy]-3,7-dimethyl-2-octenyl]oxy]-7H-furo[3,2-g][1]benzopyran-7-one (GF-I-4) to have 5-geranyloxyfurocoumarin dimer structures [14].
Grapefruits are natural products and, thus, the furocoumarin contents are expected to show considerable changes among the juices. In addition, wide variation are known on the consequence of grapefruit juice-induced drug interaction [8], [9]. Grapefruit juices are daily consumed and often taken together with drugs. Therefore, differences in furocoumarin contents in commercial grapefruit juice and grapefruit itself have been investigated as a basis of prediction for grapefruit–drug interaction in the present study.
Section snippets
Apparatus
All mass spectra were obtained using a MStation 700 tandem type mass spectrometer (JOEL, Japan) equipped with an electrospray ionization source. An HPLC model HP1100 system (Hewlett-Packard, USA) was used. For ESI/MS analysis, the temperatures of the desolvating plate and orificel were set at 200°C and 80°C, respectively. The voltages of the ring lens and orificel were set at 90 V and 50 V, respectively. ESI/MS was carried out using nitrogen to assist nebulization. Collisionally-induced
Calibration and recovery
An adequate separation of all analytes were achieved as shown in Fig. 2. Linearity of GF-I-1, GF-I-2 and GF-I-4 was evaluated over the range 10.1–324.0 ng per injection for GF-I-1 and GF-I-4, and 101.3–3240.0 ng per injection for GF-I-2. The calibration curves of GF-I-1, GF-I-2 and GF-I-4 were y=0.00108x+0.00368 (r=0.999), y=0.00115x+0.0444 (r=0.999) and y=0.00100x+0.00224 (r=0.999), respectively. The intra-day variability of GF-I-1, GF-I-2 and GF-I-4 are summarized in Table 1. The intra-day
Discussion
Coadministration of grapefruit juice with drugs, metabolized mainly by CYP3A4, has been reported to result in substantial increases in their oral bioavailabilities [1], [2], [3], [4], [5]. This phenomenon occurred through the inhibition of CYP3A4. In our previous study [14], GF-I-1 and GF-I-4 were shown to inhibit microsomal testosterone 6β-hydroxylation in human livers. The present study indicates that GF-I-1 and GF-I-4 are specifically contained in grapefruit juice, but not in other fruit
Definition list
- HPLC
high-performance liquid chromatography
- CYP and P450
cytochrome P450
- LC/MS/MS
liquid chromatography/tandem mass spectrometry
- NMR
nuclear magnetic resonance
- CID
collisionally induced dissociation
- H–D
hydrogen–deuterium
- GF-I-1
4-[[6-hydroxy-7-[[1-[(1-hydroxy-1-methyl)ethyl]-4-methyl-6-(7-oxo-7H-furo[3,2-g][1]benzopyran-4-yl)-4-hexenyl]oxy-3,7-dimethyl-2-octenyl]oxy]-7H-furo[3,2-g][1]benzopyran-7-one
- GF-I-4
4-[[6-hydroxy-7-[[4-methyl-1-(1-methylethenyl)-6-(7-oxo-7H-furo[3,2-g
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2017, Journal of Food and Drug AnalysisCitation Excerpt :Their results showed that the concentrations of bergamottin, 6′,7′-dihydroxybergamottin, and epxoybergamottin ranging from 2.4 μg/mL to 10 μg/mL, from 0.3 μg/mL to 12.8 μg/mL, and from 0.17 μg/mL to 0.27 μg/mL, respectively, whereas the amounts of furanocoumarin dimers, paradisin A, B, and C, were relatively lower than bergamottin. A previous study also indicated that concentrations of furanocoumarins in white grapefruits were typically higher than those from red grapefruits [46,56]. Furanocoumarin concentrations in 29 white and 29 red commercial grapefruit juice from the retail market have been previously compared [44].
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2015, Food ChemistryCitation Excerpt :From 58 commercial grapefruit juices of 2 seasons, Widmer and Haun (2005) found that bergamottin contents in white grapefruit juice were higher than that in red grapefruit juice, and shelf-stable juice contained less 6,7-DHB and OSE1 & 2 dimer but had higher levels of bergamottin and OSE3 compared with refrigerated juice. Fukuda, Guo, Ohashi, Yoshikawa, and Yamazoe (2000) also reported that there were lower levels of GF-I-1, GF-I-2 and GF-I-4 in red grapefruit juice compared with white grapefruit juice; and the accumulations of the 3 compounds were high in the fruit tissues of grapefruit, low in lemon juice, while undetectable in orange and tangerine juice. Cancalon, Barros, Haun, and Widmer (2011) reported that heating and storage temperature have greater impacts on the furanocoumarin contents in both the fruit and juice of grapefruit, and the contents change obviously with the prolonging of storage time.
Variability in response to drugs
2015, Journal of Pain and Symptom ManagementMajor furocoumarins in grapefruit juice I: Levels and urinary metabolite(s)
2011, Food and Chemical ToxicologyCitation Excerpt :Furthermore, we suggested a Photo-Mutagenicity Equivalency Factor (PMEF) system which attributes each furocoumarin with a factor describing its relative photomutagenicity in V79 cells under standard conditions (Raquet and Schrenk, 2009; Lohr et al., 2010). Grapefruit juice was reported (Murray et al., 1982) to contain bergamottin as the major furocoumarin and a number of minor furocoumarin constituents, i.e. 6′7′-dihydroybergamottin (DHB), and three furocoumarin dimers (Edwards et al., 1996; Fukuda et al., 2000; He et al., 1998) as well as minor amounts of 6′,7′-epoxybergamottin (Manthey and Buslig, 2005). In previous reports Mohri and Uesawa (2001) and Uesawa and Mohri (2006) found bergamottin, bergaptol and DHB as major furocoumarins in grapefruit juice.