Effect Of Grapefruit Juice Research Articles

Anti-inflammatory and Antioxidant Effects of Grapefruit Juice on Ulcerative Colitis induced by Acetic Acid in Rats

Grapefruit is commonly consumed around the world due to its nutritional and medicinal properties. Ulcerative colitis (UC) accounts for an inflammatory bowel disease (IBD) accompanied by irritation, recurrent inflammation, and ulceration of the colon's mucosa. Our objective was to assess the antiinflammatory and antioxidant impacts of grapefruit juice (GFJ) in rat with UC induced by acetic acid (AA). There were five groups made up of 35 mature male rats. Group 2 served as a positive control with UC, whereas group 1 was preserved as a negative control. For 8 weeks, groups 3, 4, and 5 received UC while also given 2.5, 5 or 10% of GFJ orally. Feed efficiency ratio (FER), body weight growth (BWG), and feed intake (FI) were computed. From rat eye orbital plexuses blood samples were taken to separate the serum after centrifugation. The aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activity were assessed utilizing serum samples. The antioxidant enzymes catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD) in serum were quantified. Serum inflammatory cytokines as tumor necrosis factor alpha (TNFα), interleukin 1 β (IL1 β), IL6 and IL8, as well as triglycerides (TG) and total cholesterol (TC) were measured. In liver homogenate, glutathione (GSH) and malondialdehyde (MDA) were determined. Additionally, histopathology of the colon was accomplished. Our findings specified that GFJ at 10% significantly decreased FI, BWG and FER, cytokines TNFα, IL1 β, IL6 and IL8 and TC and TG. Relative to the positive controls, the rats treated with GFJ exhibited elevated serum concentrations of SOD, GPx, and CAT enzymes. Liver GSH was elevated and MDA was reduced. Histopathological examination of the colon showed that GFJ at 10% reduced ulcerative colitis. Because grapefruit juice has strong anti-inflammatory and antioxidant characteristics and reduces oxidative stress and inflammation in rats, grapefruit juice, at a concentration of 10%, likely protects against ulcerative colitis. Patients with ulcerative colitis may find it helpful to consume grapefruit juice as a beverage.

Network Analysis of the Herb-Drug Interactions of Citrus Herbs Inspired by the "Grapefruit Juice Effect".

This study was performed to investigate the herb–drug interactions (HDIs) of citrus herbs (CHs), which was inspired by the “grapefruit (GF) juice effect”. Based on network analysis, a total of 249 components in GF and 159 compounds in CHs exhibited great potential as active ingredients. Moreover, 360 GF-related genes, 422 CH-related genes, and 111 genes associated with drug transport and metabolism were collected, while 25 and 26 overlapping genes were identified. In compound–target networks, the degrees of naringenin, isopimpinellin, apigenin, sinensetin, and isoimperatorin were higher, and the results of protein–protein interaction indicated the hub role of UGT1A1 and CYP3A4. Conventional drugs such as erlotinib, nilotinib, tamoxifen, theophylline, venlafaxine, and verapamil were associated with GF and CHs via multiple drug transporters and drug-metabolizing enzymes. Remarkably, GF and CHs shared 48 potential active compounds, among which naringenin, tangeretin, nobiletin, and apigenin possessed more interactions with targets. Drug metabolism by cytochrome P450 stood out in the mutual mechanism of GF and CHs. Molecular docking was utilized to elevate the protein–ligand binding potential of naringenin, tangeretin, nobiletin, and apigenin with UGT1A1 and CYP3A4. Furthermore, in vitro experiments demonstrated their regulating effect. Overall, this approach provided predictions on the HDIs of CHs, and they were tentatively verified through molecular docking and cell tests. Moreover, there is a demand for clinical and experimental evidence to support the prediction.

Effect of grapefruit juice on CYP2E1 gene expression in obese and control rats

Background and Aims: The CYP2E1 gene encodes cytochrome P450 enzymes that play an essential role in liver fat metabolism. Additionally, grapefruit reduces plasma lipids in the body. Therefore, herbal medicines can be considered as an important treatment strategy. The present study aimed to evaluate the effect of grapefruit juice on CYP2E1 gene expression in obese and control rats. Materials and Methods: This experimental study was performed on 24 male Wistar rats weighing 180±20 g. Rats were divided into four groups: control (no treatment), high-fat diet group, treatment group 1 (high cholesterol diet with grapefruit juice 4 ml/kg), and treatment group 2 (high-fat diet with grapefruit juice) (8 ml/kg). They also gavaged for 6 weeks and CYP2E1 gene expression was finally determined. Statistical analyzes were performed using SPSS software (version 22). Results: The results of CYP2E1 gene expression indicated that grapefruit juice at a dose of 8 ml/kg can further reduce the expression of CYP2E1 gene in rats with fatty liver (1.09 ±0.038) than the dose of 4 ml/kg (1.27 ±0.24). This reduction in expression was statistically significant compared to that of the high-fat diet group (3.61 ±0.25) (P=0.003). Conclusion: The results of this study demonstrated that grapefruit juice reduces the expression of the CYP2E1 gene in obese rats due to naringin and recovers the disease by reducing the accumulation of triglycerides in the liver. Therefore, grapefruit juice can be considered as a therapeutic target in fatty liver disease and obesity.

Uricostatic and uricosuric effect of grapefruit juice in potassium oxonate‐induced hyperuricemic mice

The aim of this study was to examine the preventive action of grapefruit juice (GFJ) against potassium oxonate-induced hyperuricemic mice. The results showed that GFJ significantly (p<.05) inhibit the serum and hepatic xanthine oxidase enzyme, lower uric acid level, serum creatinine, uromodulin, and blood urea nitrogen levels to normal and lower inflammation related genes IL-1β, caspase-1, NLRP3, and ASC. Furthermore, histopathology analysis revealed that GFJ markedly improve the renal and intestinal morphology. The mRNA expression of urate transporter 1, glucose transporter 9 were downregulated, whereas ATP-binding cassette transporter (ABCG2) was upregulated in the GFJ-treated group. The results of immunohistochemistry revealed that the ABCG2 protein expression in the small and large intestine was significantly upregulated after the GFJ administration. These results suggested that GFJ can be used as a urate lowering agent and future mechanistic studies should be conducted. PRACTICAL APPLICATIONS: The results of current study indicated that utilization of GFJ as an anti-hyperuricemic agent for the treatment of hyperuricemia. This article will be very valuable for all those peoples which are directly or indirectly linked with this disease.

The Effect of Grapefruit Juice on the Pharmacokinetics of Tadalafil in Rats.

We developed and validated a novel, sensitive, selective, and inexpensive high-performance liquid chromatography (HPLC) method for the determination of tadalafil in rats plasma and to investigate the effect of grapefruit juice on the pharmacokinetics of tadalafil in rats. The ZORBAX Eclipse XDB-C18 (4.6 × 150 mm, 5 μm) chromatography column can be used to separate tadalafil and carbamazepine (internal standard, IS). A mixture of acetonitrile-0.2% trifluoroacetic acid-water (48 : 10 : 42, V/V/V) was used as the mobile phase with a flow rate of 1.0 mL/min. The column temperature was set at 35.0°C. The detection wavelength was set at 286 nm. The tadalafil was extracted by ethyl acetate from plasma at the alkaline condition. 12 healthy male Sprague-Dawley (SD) rats were randomly divided into two groups, Group A (experimental group, received grapefruit juice 5 mL/kg for 7 days) and Group B (control group, received normal saline for 7 days). All the rats were given a single dose of tadalafil (5 mg/kg) after the last administration. The main pharmacokinetic parameters were calculated by DAS 2.0 software. Under the conditions of this experiment, the plasma concentrations of tadalafil in the range of 10–2000 ng/ml had a good linear relationship. The intra- and interday precision for tadalafil in plasma were less than 15%, and the relative recovery rate was good at low, medium, and high QC levels. The Cmax of tadalafil in the control group and the experimental group was (725.89 ± 161.59) ng/mL and (1271.60 ± 179.31) ng/mL, t1/2 was (9.28 ± 2.07) h and (11.70 ± 1.47) h, AUC (0-t) was (7399.61 ± 696.85) ng·h/mL and (9586.52 ± 2048.81) ng·h/mL, and AUC(0-∞) was (7995.50 ± 707.23) ng·h/mL and (10639.43 ± 2235.94) ng·h/mL, respectively. Results show that the Cmax of tadalafil in group A was 75.17% higher than that in group B, the Vz/F was also reduced, and the t1/2 was increased by 2.42 h. The developed HPLC–DAD method for the determination of tadalafil in rats plasma was accurate, reproducible, specific, and it was found to be suitable for the pharmacokinetics of tadalafil and food-drug interactions. Grapefruit juice can inhibit the metabolism of tadalafil and increase the exposure of tadalafil in rats.

Grapefruit juice prolongs the QT interval of healthy volunteers and patients with long QT syndrome

The list of medications linked to drug-induced long QT syndrome (LQTS) is diverse. It is possible that food products too have QT-prolonging potential. We tested the effects of grapefruit juice on the QT interval with the methodology used by the pharmaceutical industry to test new drugs. This was an open-label, randomized, crossover study with blinded outcome evaluation, a thorough QT study of grapefruit juice performed according to the Guidelines for the Clinical Evaluation of QT/QTc for Non-antiarrhythmic Drugs. Thirty healthy volunteers and 10 patients with congenital LQTS were studied. Healthy volunteers drank 2 L of grapefruit juice (in divided doses), or received 400 mg oral moxifloxacin, in a randomized crossover study. Patients with LQTS were tested with only grapefruit. Repeated baseline, off-drug, and on-drug (grapefruit or moxifloxacin) electrocardiograms were scanned and coded. QT measurements were done with electronic calipers. In comparison to off-drug electrocardiograms, grapefruit juice led to significant rate-corrected QT (QTc) prolongation. The absolute net QTc prolongation from grapefruit was 14.0 ms (95% confidence interval 6.2-21.7 ms; P < .001). The QT-prolonging effects of grapefruit in healthy volunteers were comparable with those of moxifloxacin. The QT-prolonging effects of grapefruit juice were greater in female patients and particularly marked in patients with LQTS (net QTc prolongation 21.8 ms; 95% confidence interval 3.4-35.3 ms; P = .034). Grapefruit juice, at doses tested, prolongs the QT interval. The effect is significant in healthy volunteers, greater in female patients, and more so in patients with LQTS.

Effect of Grapefruit Juice Intake on Serum Level of the Endogenous CYP3A4 Metabolite 4β-Hydroxycholesterol-an Interaction Study in Healthy Volunteers.

4β-Hydroxycholesterol (4βOHC) is an endogenous CYP3A4 metabolite. However, it is unclear whether circulating levels of 4βOHC may reflect hepatic CYP3A4 activity or both hepatic and intestinal enzyme activity. The aim of this study was to investigate the effect of grapefruit juice, regarded to be a selective intestinal CYP3A4 inhibitor, on serum 4βOHC levels in healthy volunteers. The participants (n = 22) consumed grapefruit juice twice daily for 3weeks followed by a 2-week washout period. Blood samples for measurements of 4βOHC and the non-CYP3A4-derived oxysterols 24-hydroxycholesterol (24OHC) and 27-hydroxycholesterol (27OHC), as well as lathosterol and total cholesterol, were drawn on days 0, 7, 21, and 35. Median individual changes (ratios) in cholesterol-corrected 4βOHC levels from baseline to weeks 1, 3, and 5 were 0.94 (P = 0.2), 0.98 (P = 0.3), and 0.97 (P = 0.9), respectively. In comparison, median changes (ratios) in cholesterol-corrected levels of 24OHC at the same points were 1.01 (P = 0.6), 0.98 (P = 0.3), and 0.99 (P = 0.5), and of 27OHC 1.01 (P = 0.8), 0.97 (P = 0.5), and 0.99 (P = 0.2). Surprisingly, serum concentration of cholesterol was significantly reduced by approximately 5% after 1week (P = 0.03), while median cholesterol-corrected levels of lathosterol increased significantly and persistently by approximately 15% during the whole 5-week period (P < 0.04). In conclusion, the present findings suggest that intestinal CYP3A4 is not relevant for the overall formation of 4βOHC in healthy volunteers. The fact that grapefruit juice altered cholesterol homeostasis should be further investigated.

Potentiating and synergistic effect of grapefruit juice on the antioxidant and anti-inflammatory activity of aripiprazole against hydrogen peroxide induced oxidative stress in mice

BackgroundDependence on antipsycotic drugs like aripriprazole (ARI) is increasing at alarming rate, hence, this study was undertaken to support the hypothesis that supplementation of Citrus paradisi(Grapefruit) juice having high concentration of polyphenols might potentiate and synergize the therapeutic effect of ARI, by increasing its bioavailability and inherent antioxidant potential. These benefits together might decrease the daily dosage of the ARI and thus alleviate the possible side effects of drug.MethodsIn this study the antioxidant and anti-inflammatory potential of ARI alone and in combination with GFJ was evaluated for hydrogen peroxide (H2O2) induced oxidative stress in mice. Seventy mice (4 weeks old), were randomly divided into seven groups. Group I: Control; Group II: H2O2 treated; Group III; ARI treated; Group IV GFJ treated; Group V: GFJ and H2O2 treated; Group VI; ARI and H2O2 treated; Group VII; ARI, GFJ and H2O2 treated. Serum levels of alanine aminotransferase (ALT), blood urea nitrogen (BUN), creatinine kinase (CK), creatinine and total protein were measured. Furthermore, pro-inflammatory cytokines Interleukin (IL)-1α, IL-2, IL-10 and tumor necrosis factor-α (TNF-α) concentrations were also measured.ResultsThe mice group that was treated with ARI, GFJ or combination of the two showed significant improvement in the H2O2 altered parameters with the combination group showing more significant improvement than the ARI and GFJ alone groups indicating a synergistic and potentiating effect of the antioxidant and anti-inflammatory potential of GFJ on ARI.ConclusionSupplementing GFJ to ARI might increase an anti-oxidative potential of ARI due to inherent antioxidant and anti-inflammatory activity of GFJ and thus could alleviate the possible dosage dependent side effects of ARI.

Effect of Grapefruit Juice on Aluminum-Induced Hepatotoxicity in Albino Rats: Histological, Ultrastructural and Histochemical Assessment

The present work studied the effect of grapefruit juice (Citrus) on the hepatotoxicity of AlCl3. Four groups of adult male albino rats were used. Group I contained 10 rats and remained as a control group; Group II: 10 rats were included and orally administered with grapefruit juice at a dose level of 27 ml/kg of body weight per day for 6 weeks; Group III: 10 rats were included and AlCl3 was administered orally at a dose level of 100 mg/kg of body weight per day for 6 weeks; Group IV: animals of this group (10 rats) were given a combination of AlCl3 and grapefruit juice per day for 6 weeks. At the end of the sixth week, the liver was processed for histological and ultrastructure studies. In addition, ALT and AST were determined in blood sera. The results showed that AlCl3 induced several histological alterations in the liver, including congestion of blood vessels, leucocytic infiltration, cytoplasmic vacuolation of hepatocytes and fatty infiltrations. Ultrastructural changes include the degeneration of mitochondria, RER swelling and pyknosis of the nuclei with an increase in fat droplets and lysosomes. The biochemical results showed an increase in ALT and AST activities in the AlCl3 group. However, the group of rats treated with AlCl3 and grapefruit juice improved the histological and ultrastructural changes, while the levels of ALT and AST were reduced. It was concluded in the results that grapefruit juice has a protective effect against hepatotoxicity of AlCl3 that can be attributed to the antioxidant properties of its components.

Clementine juice has the potential for drug interactions – In vitro comparison with grapefruit and mandarin juice

Adverse drug interactions due to grapefruit juice are well known prompting warnings even in drug labels. Similar issues have not been reported for clementines and available data is scarce, despite of genetic descent. We observed substantially increased tacrolimus trough concentrations in a renal transplant patient consuming high clementine amounts and, thus, scrutinised the effects of clementine juice on drug metabolism and drug transporters in vitro and compared it to the effects of mandarin and grapefruit juice. All citrus juices profoundly induced several drug transporters and drug metabolising enzymes, whereas the effects of grapefruit juice were most pronounced (e.g. 156-fold and 34-fold induction of cytochrome P450 (CYP) 3A4 mRNA by grapefruit juice and clementine juice, respectively). However, the juices also inhibited e.g. CYP3A4, raising the question which effect prevails in vivo. Using an enzymatic activity assay, we demonstrated that at least in vitro CYP3A4 inhibition prevails for both grapefruit and clementine juice, whereas for CYP1A2 induction appears to predominate. Thus, inhibition of CYP3A4 is presumably the underlying reason for the observed increase in the concentrations of the CYP3A4 substrate tacrolimus in the patient. Taken together, our data indicate that clementine juice as well as grapefruit juice and to a lesser extent also mandarin juice can induce several important drug metabolising enzymes and drug transporters, but also inhibit some of these proteins. Our data indicate that clementine juice similar to grapefruit juice bears the potential for profound interactions with drugs potentially leading to adverse drug effects e.g. through over-exposure to CYP3A4 substrates.

Effect of Low-Furanocoumarin Hybrid Grapefruit Juice Consumption on Midazolam Pharmacokinetics.

The objectives of this study were to investigate the effect of grapefruit juice low in furanocoumarins on CYP3A activity and to summarize previous findings of enzyme inhibition measured by the metabolism of midazolam after intake of grapefruit juice. Twelve healthy volunteers participated in a prospective, randomized, double-blinded, 3-way crossover clinical study to determine the effect of regular grapefruit juice (RGJ) and a novel, low-furanocoumarin hybrid grapefruit juice (HGJ) on the metabolism of oral midazolam, used as a probe for in vivo CYP3A activity, compared with water as a control. The RGJ was 100% hand-squeezed "Hudson" grapefruit juice, and the HGJ contained low amounts of furanocoumarin constituents. The point estimates (90% confidence intervals) for the RGJ/water midazolam AUC geometric mean ratio was 122% (107-140). The point estimate for the HGJ/water midazolam AUC ratio was within the 80% to 125% bioequivalence range, indicating an absence of interaction. This finding also prompted a systematic review of available evidence on the pharmacokinetic alteration of midazolam by grapefruit juice. Although most studies demonstrated alteration in midazolam pharmacokinetics supporting inhibition of CYP3A activity as a likely mechanism, the cohorts included in these studies and the extent of the pharmacokinetic interaction varied widely. The current study indicated grapefruit juice-drug interaction varies substantially based on patient characteristics and/or grapefruit juice product-related factors, including the amount of furanocoumarin constituents present in the juice.

Grapefruit Derived Flavonoid Naringin Improves Ketoacidosis and Lipid Peroxidation in Type 1 Diabetes Rat Model.

BackgroundHypoglycemic effects of grapefruit juice are well known but the effects of naringin, its main flavonoid on glucose intolerance and metabolic complications in type 1 diabetes are not known.ObjectivesTo investigate the effects of naringin on glucose intolerance, oxidative stress and ketonemia in type 1 diabetic rats.MethodsSprague-Dawley rats divided into 5 groups (n = 7) were orally treated daily with 3.0 ml/kg body weight (BW)/day of distilled water (group 1) or 50 mg/kg BW of naringin (groups 2 and 4, respectively). Groups 3, 4 and 5 were given a single intra-peritoneal injection of 60 mg/kg BW of streptozotocin to induce diabetes. Group 3 was further treated with subcutaneous insulin (4.0 IU/kg BW) twice daily, respectively.ResultsStretozotocin (STZ) only-treated groups exhibited hyperglycemia, polydipsia, polyuria, weight loss, glucose intolerance, low fasting plasma insulin and reduced hepatic glycogen content compared to the control group. Furthermore they had significantly elevated Malondialdehyde (MDA), acetoacetate, β-hydroxybutyrate, anion gap and significantly reduced blood pH and plasma bicarbonate compared to the control group. Naringin treatment significantly improved Fasting Plasma Insulin (FPI), hepatic glycogen content, malondialdehyde, β-hydroxybutyrate, acetoacetate, bicarbonate, blood pH and anion gap but not Fasting Blood Glucose (FBG) compared to the STZ only-treated group.ConclusionsNaringin is not hypoglycemic but ameliorates ketoacidosis and oxidative stress. Naringin supplements could therefore mitigate complications of diabetic ketoacidosis.

Stable isotope-labelled intravenous microdose for absolute bioavailability and effect of grapefruit juice on ibrutinib in healthy adults.

Ibrutinib, an inhibitor of Bruton's tyrosine kinase, is used in the treatment of mantle cell lymphoma or chronic lymphocytic leukaemia. Ibrutinib undergoes extensive rapid oxidative metabolism mediated by cytochrome P450 3A both at the level of first pass and clearance, which might result in low oral bioavailability. The present study was designed to investigate the absolute bioavailability (F) of ibrutinib in the fasting and fed state and assess the effect of grapefruit juice (GFJ) on the systemic exposure of ibrutinib in order to determine the fraction escaping the gut (Fg ) and the fraction escaping hepatic extraction (Fh ) in the fed state. All participants received treatment A [560mg oral ibrutinib, under fasting conditions], B (560mg PO ibrutinib, fed, administered after drinking glucose drink) and C (140mg oral ibrutinib, fed, with intake of GFJ before dosing). A single intravenous (i.v.) dose of 100μg (13) C6 -ibrutinib was administered 2h after each oral dose. The estimated 'F' for treatments A, B and C was 3.9%, 8.4% and 15.9%, respectively. Fg and Fh in the fed state were 47.0% and 15.9%, respectively. Adverse events were mild to moderate in severity (Grade 1-2) and resolved without sequelae by the end of the study. The absolute oral bioavailability of ibrutinib was low, ranging from 3.9% in the fasting state to 8.4% when administered 30min before a standard breakfast without GFJ and 15.9% with GFJ. Ibrutinib was well tolerated following a single oral and i.v. dose, under both fasted and fed conditions and regardless of GFJ intake status.

The Distribution of Coumarins and Furanocoumarins in Citrus Species Closely Matches Citrus Phylogeny and Reflects the Organization of Biosynthetic Pathways.

Citrus plants are able to produce defense compounds such as coumarins and furanocoumarins to cope with herbivorous insects and pathogens. In humans, these chemical compounds are strong photosensitizers and can interact with medications, leading to the “grapefruit juice effect”. Removing coumarins and furanocoumarins from food and cosmetics imply additional costs and might alter product quality. Thus, the selection of Citrus cultivars displaying low coumarin and furanocoumarin contents constitutes a valuable alternative. In this study, we performed ultra-performance liquid chromatography coupled with mass spectrometry analyses to determine the contents of these compounds within the peel and the pulp of 61 Citrus species representative of the genetic diversity all Citrus. Generally, Citrus peel contains larger diversity and higher concentrations of coumarin/furanocoumarin than the pulp of the same fruits. According to the chemotypes found in the peel, Citrus species can be separated into 4 groups that correspond to the 4 ancestral taxa (pummelos, mandarins, citrons and papedas) and extended with their respective secondary species descendants. Three of the 4 ancestral taxa (pummelos, citrons and papedas) synthesize high amounts of these compounds, whereas mandarins appear practically devoid of them. Additionally, all ancestral taxa and their hybrids are logically organized according to the coumarin and furanocoumarin pathways described in the literature. This organization allows hypotheses to be drawn regarding the biosynthetic origin of compounds for which the biogenesis remains unresolved. Determining coumarin and furanocoumarin contents is also helpful for hypothesizing the origin of Citrus species for which the phylogeny is presently not firmly established. Finally, this work also notes favorable hybridization schemes that will lead to low coumarin and furanocoumarin contents, and we propose to select mandarins and Ichang papeda as Citrus varieties for use in creating species devoid of these toxic compounds in future breeding programs.

Effect of grapefruit juice and food on the pharmacokinetics of pirfenidone in healthy Chinese volunteers: a diet–drug interaction study

1. Ingestion of grapefruit juice and food could be factors affecting the pharmacokinetics of pirfenidone, a promising drug for treatment of idiopathic pulmonary fibrosis.2. A randomized, open-label, three-period crossover study was carried out in 12 healthy Chinese male volunteers who were randomized to one of the three treatments: pirfenidone tablets (0.4 g) were orally administered to fasted or fed subjects, or with grapefruit juice. The washout period was 7 d.3. Significantly reduced maximum plasma concentration (Cmax, 5.0 5 ± 1.39 versus 10.9 0 ± 2.94 mg·L− 1), modestly affected area-under-the-plasma concentration–time curve (AUC) from time zero to 12 h post dosing (AUC0–12 h, 21.8 9 ± 6.47 versus 26.1 6 ± 7.32 mg·h·L− 1) and delayed time to reach Cmax (Tmax) were observed in fed group compared with fasted group. Similar effects on Cmax (5.8 2 ± 1.23 versus 10.9 0 ± 2.94 mg·L− 1) and AUC0–12 h (modest but not statistically significant, 24.4 4 ± 7.40 versus 26.1 6 ± 7.32 mg·h·L− 1) were observed for grapefruit juice compared to fasted subjects.4. Co-administration of pirfenidone with grapefruit juice resulted in modestly reduced overall oral absorption and significantly reduced peak concentrations compared to fasting, which was similar to effect of food ingestion. No adverse events were observed in the study, but relatively dramatic reduction of peak concentrations should raise concerns for clinical efficacy and safety.

Effect of grapefruit juice on the bioactivation of prasugrel.

The P2Y12 inhibitor prasugrel is a prodrug, which is activated after its initial hydrolysis partly by cytochrome P450 (CYP) 3A4. Grapefruit juice, a strong inactivator of intestinal CYP3A4, greatly reduces the activation and antiplatelet effects of clopidogrel. The aim of this study was to investigate the effects of grapefruit juice on prasugrel. In a randomized crossover study, seven healthy volunteers ingested 200 ml of grapefruit juice or water three times daily for 4 days. On day 3, they ingested a single 10 mg dose of prasugrel with an additional 200 ml of grapefruit juice or water. Plasma concentrations of prasugrel metabolites and the antiplatelet effect were measured. Grapefruit juice increased the geometric mean area under the plasma concentration-time curve (AUC(0-∞)) of the primary, inactive metabolite of prasugrel to 164% of the control value (95% confidence interval 122-220%, P = 0.008), without a significant effect on its peak plasma concentration (C(max)). The C(max) and AUC(0-∞) of the secondary, active metabolite were decreased to 51% (95% confidence interval 32-84%, P = 0.017) and 74% of the control value (95% confidence interval 60-91%, P = 0.014) by grapefruit juice (P < 0.05). The average platelet inhibition, assessed with the VerifyNow® method at 0-24 h after prasugrel intake, was 5 percentage points (95% confidence interval 1-10 percentage points) lower in the grapefruit juice phase than in the water phase (P = 0.034). Grapefruit juice reduces the bioactivation of prasugrel, but this has only a limited effect on the antiplatelet effect of prasugrel.

Content evaluation of 4 furanocoumarin monomers in various citrus germplasms

Due to the furanocoumarin compounds in the fruit, the production and consumption of grapefruit have been affected in the past decades since the ‘grapefruit juice effect’ was declared. To provide elite germplasm and obtain knowledge for future citrus breeding programs, the contents of 4 furanocoumarin monomers (FCMs) in the juice sacs from 73 citrus germplasms were evaluated using ultra-performance liquid chromatography. 6′,7′-Dihydroxybergamottin and bergamottin were dominant in all the tested grapefruits, while there were some pomelos with dominant epoxybergamottin, and some with dominant 6′,7′-dihydroxybergamottin and bergamottin. The contents of FCMs were low or below detection in sweet oranges, mandarins, lemons and trifoliate oranges. The results also show that the dominant patterns of FCMs are genotype-related, and crossing and selection are effective approaches to alter FCM profiles in citrus breeding. Furthermore, the contribution of pomelo as a parent to grapefruit regarding their FCM profiles was discussed.

Grapefruit juice improves glucose intolerance in streptozotocin-induced diabetes by suppressing hepatic gluconeogenesis.

Hypoglycemic effects of grapefruit juice (GFJ) are widely recognized, but the mechanism(s) by which GFJ lowers blood glucose levels have not previously been investigated. Wistar rats [250-300 g body weight (BW)] were divided into eight groups (n = 7). Group 1 animals were orally treated with 3.0 ml/kg BW of distilled water for 60 days, while groups 3, 4, 5, 6 were similarly treated with 3.0 ml/kg BW of GFJ. Groups 4 and 7 as well as 2, 5, 6 and 8 were given 45.0 and 60.0 mg/kg BW intraperitoneal injections streptozotocin, respectively, while groups 2 and 6 animals were additionally injected with insulin (4.0 units/kg, S.C., b.d), respectively. Fasting blood glucose (FBG) and glucose tolerance tests were done. Hepatic glycogen content and glucokinase, glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) activities were measured in homogenized liver tissues. Diabetic rats, groups 2 and 4-8 exhibited significantly reduced weight gain but increased polydipsia compared to controls. FBG was significantly increased in diabetic rats compared to controls but were significantly improved in GFJ-treated-compared to non-treated-diabetic rats. Similarly, diabetic rats showed significant glucose intolerance compared to controls which was improved by GFJ treatment. GFJ treatment did not improve fasting plasma insulin in diabetic rats. GFJ treatment significantly elevated glucokinase activity and hepatic glycogen concentrations but suppressed the activities of G6Pase and PEPCK, respectively, in diabetic animals. These findings show that GFJ is not insulinotropic but improves glucose intolerance in diabetic rats by suppressing hepatic gluconeogenesis.

English

Grapefruit (Citrus Paradise, family Rutaceae) is a citrus fruit that is low in calories and rich in dietary fibers. Sibutramine (Sibutramine hydrochloride monohydrate) is an anti-obesity drug that enhances satiety. The effect of grapefruit juice and sibutramine on body weight and neurotransmitters controlling appetite was investigated in obese rats. &nbsp;Rats were assigned to two dietary groups for 3 weeks; control group (n=6) was fed commercial standard pellets diet and obese group (n=24) was fed cafeteria diet (hypercaloric diet consisting of highly palatable food). The effect of sibutramine and grapefruit juice was studied on obese rats. Statistical difference and interactions were evaluated through one-way analysis of variance test (one-way ANOVA) followed by Dunnett&rsquo;s test was used for means of different groups. For all statistical tests done, a 0.05 level of probability was used as the criterion for significance. Grapefruit juice produced its weight reduction effect after 1 week of administration and lasted till the end of the experiment and did not affect brain neurotransmitters. Sibutramine produced its weight reduction effect after 1 week of administration and lasted for only 2 weeks and produced an increase in brain noradrenaline while grapefruit juice produced its effect from the first week till the end of the study. It can be concluded that grapefruit juice is better than sibutramine since its effect lasted till the end of the experiment and also did not affect brain noradrenaline. &nbsp;Key words: Obesity, sibutramine, grapefruit juice, cafeteria diet.

Effects of grapefruit juice on cortisol metabolism in healthy male Chinese subjects

Grapefruit juice (GFJ) inhibits intestinal CYP3A4 activity and it has been suggested that GFJ may also inhibit renal 11β-hydroxysteroid dehydrogenase 2 (11β-HSD2), which converts cortisol to cortisone. This study examined the effect of GFJ on the urinary excretion of cortisol, cortisone and 6β-hydroxycortisol (6β-OHC) and their ratios to asses these effects. Healthy male Chinese subjects took single doses of GFJ (200, 400, and 600 mL, respectively) at weekly intervals. Urine was collected over 24 h the day before and following GFJ intake. Subsequently, volunteers drank 400 mL GFJ for 7 days and urine was collected from 0 to 4 h daily. GFJ had dose-dependent effects on increasing cortisol excretion (P < 0.05) and the ratio of cortisol to cortisone (P < 0.005) and reducing 6β-OHC excretion (P < 0.05) and the ratio of 6β-OHC to cortisol (P < 0.005). There was no significant effect on cortisone excretion. Maximal effects were observed within 4 h after GFJ ingestion. Repeated doses had persistent but no cumulative effects. GFJ significantly reduced the ratio of 6β-OHC to cortisol. It increased the ratio of cortisol to cortisone and this appeared largely due to increased cortisol excretion related to impaired CYP3A4-mediated cortisol metabolism although a true inhibitory effect on 11β-HSD2 in the kidney cannot be excluded.