Ingestion Of Grapefruit Juice Research Articles

Quinine sensitivity influences the acceptance of sea-buckthorn and grapefruit juices in 9- to 11-year-old children

The acceptance of novel foods by children is related to a number of factors, and differences in taste sensitivity may form some specific challenges. High sensitivity might be a barrier to the acceptance of sour/bitter products by children. This study investigated the effect of sensitivity to bitter, sour, sweet, and salty tastes on the acceptance of Nordic juices in 9- to 11-year-old children. A total of 328 children were subjected to two taste sensitivity tests for quinine, citric acid, sucrose, and NaCl. Their acceptance of six juices (carrot, rosehip, sea-buckthorn, lingonberry, grapefruit, and aronia) was measured. Bitter sensitivity was found to be significantly correlated to the intake of the sweet sea-buckthorn and lingonberry juices; the most bitter-sensitive children exhibited the highest intake of these juices. The opposite relationship was found for bitter sensitivity and the intake of the bitter grapefruit juice. Sour, sweet, and salt sensitivities did not affect the intake of any of the juices. Liking scores were not affected by sensitivity. In conclusion, bitter sensitivity appears to influence food intake in children to a greater extent than sour, sweet, or salt sensitivity. Bitter-sensitive children exhibited a reduced intake of grapefruit juice and a higher intake of sucrose-sweetened juices. Thus, bitter sensitivity might be a challenge in the acceptance of certain bitter foods.

Utilizing In Vitro and PBPK Tools to Link ADME Characteristics to Plasma Profiles: Case Example Nifedipine Immediate Release Formulation

One of the most prominent food-drug interactions is the inhibition of intestinal cytochrome P450 (CYP) 3A enzymes by grapefruit juice ingredients, and, as many drugs are metabolized via CYP 3A, this interaction can be of clinical importance. Calcium channel-blocking agents of the dihydropyridine type, such as felodipine and nifedipine, are subject to extensive intestinal first pass metabolism via CYP 3A, thus resulting in significantly enhanced in vivo exposure of the drug when administered together with grapefruit juice. Physiologically based pharmacokinetic (PBPK) modeling was used to simulate pharmacokinetics of a nifedipine immediate release formulation following concomitant grapefruit juice ingestion, that is, after inhibition of small intestinal CYP 3A enzymes. For this purpose, detailed data about CYP 3A levels were collected from the literature and implemented into commercial PBPK software. As literature reports show that grapefruit juice (i) leads to a marked delay in gastric emptying, and (ii) rapidly lowers the levels of intestinal CYP 3A enzymes, inhibition of intestinal first pass metabolism following ingestion of grapefruit juice was simulated by altering the intestinal CYP 3A enzyme levels and simultaneously decelerating the gastric emptying rate. To estimate the in vivo dispersion and dissolution behavior of the formulation, dissolution tests in several media simulating both the fasted and fed state stomach and small intestine were conducted, and the results from the in vitro dissolution tests were used as input function to describe the in vivo dissolution of the drug. Plasma concentration-time profiles of the nifedipine immediate release formulation both with and without simultaneous CYP 3A inhibition were simulated, and the results were compared with data gathered from the literature. Using this approach, nifedipine plasma profiles could be simulated well both with and without enzyme inhibition. A reduction in small intestinal CYP 3A levels by 60% was found to yield the best results, with simulated nifedipine concentration-time profiles within 20% of the in vivo observed results. By additionally varying the dissolution input of the PBPK model, a link between the dissolution characteristics of the formulation and its in vivo performance could be established.

Review article. Assessing clinical evidence of drug interactions between citrus juices and cyclosporine

Background: Previous studies have demonstrated that grapefruit juice increased the bioavailability of cyclosporine;however, the results from the literature are inconsistent. Other citrus fruits such as pomelo or orange juice had variable effects on the bioavailability of cyclosporine.Objective: To assess the effect of grapefruit juice and other types of citrus juice on oral bioavailability of cyclosporine in humans using meta-Analysis.Methods: We conducted a meta-Analysis of placebo-controlled studies evaluating the effects of citrus juices on bioavailability of cyclosporine. The studies were identified in PubMed, Cochrane CENTRAL, CINAHL, ISI Web of Knowledge, Psych Info International, Pharmaceutical Abstract (IPA), and reference lists of relevant papers. The weighted-mean difference (WMD) was calculated for net changes in the area under the curve (AUC) of cyclosporine. All studies conducted as placebo-controlled crossover studies in humans to compare the effect of citrus juices and control (drinking water) on AUC of cyclosporine and/or Cmin,ss were reviewed. All studies included were evaluated and extracted independently, and discrepancies were resolved through discussion.Results: Eighteen studies were identified. A subgroup analysis suggested that grapefruit juice significantly increased AUC of cyclosporine (WMD = 1762.5 ng·h/ml, 95%CI = 1178.9-2346.0 ng·h/ml, p > 0.001). While a meta-Analysis of all other types of citrus juices (tangerine juice, Seville orange juice, sweet orange juice, and citrus soda) except pomelo juice revealed no effect on the AUC of cyclosporine (WMD = -181.0 ng·h/ml,95%CI = -582.8-220.9 ng·h/ml, p > 0.5), a study of pomelo juice indicated a significant increase in the AUC of cyclosporine.Conclusions: Grapefruit juice intake increases oral bioavailability of cyclosporine in both healthy volunteers and renal transplant patients, whereas all other types of citrus juices may not have an influence on the oral bioavailability of cyclosporine. Current evidence suggests that pomelo juice may be able to increase cyclosporine oral bioavailability.

Review of Grapefruit Juice Mediated Drug-Drug Interactions – Trends from a Chirality Perspective

Prolific literature data exists on the drug-drug interaction (DDI) potential of many important xenobiotics including racemic drugs with concomitant intake of grapefruit juice (GFJ). Since recently reports have appeared that suggested that GFJ has the potential to inhibit enzymes in a stereoselective fashion, this review examines the impact of DDI studies with GFJ using examples of several racemic drugs with an emphasis on stereoselectivity in the pharmacokinetic disposition. Also, all reported mechanisms have been collated to comprehend the interaction dynamics with GFJ. Overall, the disposition of the xenobiotics regardless of chirality considerations is governed by dual interplay of cytochrome P450 and transporters in humans. Hence, the interpretation of DDI data with GFJ of chiral substrates needs to be made with caution as there is a potential for the change in the eudismic ratio due to the interaction potential. Moreover, extrapolation of either in vitro findings or preclinical data for human prediction of GFJ interactions may sometimes be misleading.

Human PXR-mediated induction of intestinal CYP3A4 attenuates 1α,25-dihydroxyvitamin D3 function in human colon adenocarcinoma LS180 cells

Oxidative catabolism of 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] is mediated by either CYP24A1 or CYP3A4. In this paper, we tested whether induction of CYP3A4 in the LS180 intestinal cell model enhances clearance of 1α,25(OH)2D3 and blunts its hormonal effect on expression of the apical membrane calcium transport protein, TRPV6. Treatment with the hPXR agonist rifampin significantly increased CYP3A4 mRNA content and catalytic activity, but had no effect on CYP24A1 or TRPV6 mRNA content. Pre-treating cells with rifampin for 48h, prior to a 24h 1α,25(OH)2D3 treatment phase, was associated with a subsequent 48% increase in the elimination of 1α,25(OH)2D3 and a 35% reduction of peak TRPV6 mRNA. Introduction of the CYP3A4 inhibitor, 6′,7′-dihydroxybergamottin, an active inhibitor in grapefruit juice, reversed the effects of rifampin on 1α,25(OH)2D3 clearance and TRPV6 expression. Over-expression of hPXR in LS180 cells greatly enhanced the CYP3A4 responsiveness to rifampin pretreatment, and elicited a greater relative suppression of TRPV6 expression and an increase in 1α,25(OH)2D3 disappearance rate, compared to vector expressed cells, following hormone administration. Together, these results suggest that induction of CYP3A4 in the intestinal epithelium by hPXR agonists can result in a greater metabolic clearance of 1α,25(OH)2D3 and reduced effects of the hormone on the intestinal calcium absorption, which may contribute to an increased risk of drug-induced osteomalacia/osteoporosis in patients receiving chronic therapy with potent hPXR agonists. Moreover, ingestion of grapefruit juice in the at-risk patients could potentially prevent this adverse drug effect.

Grapefruit consumption is associated with benefits to the intake of certain nutrients, body composition, and select physiologic parameters in U.S. women

The purpose of this study was to estimate usual intake (UI) of total grapefruit (GF) (fruit and juice) by women age 19+ y and to compare certain nutrient intakes and select health‐related parameters between consumers (GFC) and non‐consumers (GFNC) using data collected in NHANES 2003–8. GFC (n=180) were defined as women reporting intake of GF on either of 2 days of dietary recall. UI of vitamin C by GFC was significantly higher (p<0.0001) than intake by GFNC (n=6219) (145±3.9 vs 76±1.2 mg/d); UI of beta‐carotene, vitamin B6, magnesium, fiber and potassium by GFC also were higher compared to GFNC while intakes of added sugars, total fat, saturated fat and cholesterol were lower (p<0.05); energy intakes were comparable. Mean body weight (70.2±1.6 vs 75.4±0.5 kg), waist circumference (91±1.5 vs 95±0.4 cm) and BMI (26.9±0.6 vs 28.6±0.2 kg/m2) of GFC were significantly lower (p<0.01) as compared to GFNC, though the risk of overweight/obesity did not differ. HDL‐cholesterol levels were significantly higher (p<0.01) in GFC (63±1.8 vs 58±0.3 mg/dL) and triglyceride (TG) levels were lower (106±5.7 vs 130±2.5 mg/dL). There were no differences between groups in serum total or LDL‐cholesterol, blood pressure, plasma glucose or insulin. GF consumption may have a positive impact on nutrient intakes and is associated with lower body measures and higher HDL‐cholesterol among women. Supported by the Florida Department of Citrus.

Influence of CYP3A5 and MDR1 Genetic Polymorphisms on Urinary 6β‐Hydroxycortisol/Cortisol Ratio After Grapefruit Juice Intake in Healthy Chinese

Interindividual variability of cytochrome P450 (CYP) 3A inhibition by grapefruit juice was investigated in relation to CYP3A5 and multidrug resistance gene (MDR) 1 genetic polymorphisms in Chinese Han, Uygur, and Kazakh healthy subjects. The measurement of urinary 6 beta-hydroxycortisol/cortisol ratio was used to evaluate CYP3A activity in vivo by high-performance liquid chromatography. CYP3A5*3 and MDR1 C1236T, G2677T/A, and C3435T polymorphisms were analyzed by polymerase chain reaction restriction fragment length polymorphism. After grapefruit juice intake, urinary ratios significantly decreased in 3 Chinese ethnic groups (P < .001). Kazakh had a larger decrease of urinary ratio compared to that of Han (P < .05), and the latter had similar decrease with Uygur. Furthermore, Chinese healthy subjects carrying CYP3A5*3/*3 and MDR1(1236-2677-3435) T-T-T/T-T-T genotypes were found to have the largest reduction of urinary ratio (mean, 61.4%; 95% confidence interval, 53.4%-69.5%), whereas *1/*3 subjects carrying MDR1(1236-2677-3435) C-G-C/C-G-C genotypes had the lowest reduction (mean, 25.9%; 95% confidence interval, 3.1%-48.8%; P < .01). In conclusion, both CYP3A5*3 and MDR1 variants influenced the extent of CYP3A inhibition by grapefruit juice in Chinese healthy subjects. The genetic variations influencing the CYP3A inhibitive phenotype might be helpful to explain the individual variability of grapefruit juice-drug interactions.

Effects of Ingestion of Grapefruit Juice or Grapefruit on the Hypotensive Effect and Plasma Concentrations of Dihydropyridine Calcium Antagonists (Amlodipine and Nifedipine): A Case Study

The purpose of this study was to examine the effects of ingestion of grapefruit juice or grapefruit on the hypotensive effect and plasma concentration of dihydropyridine calcium antagonists, i.e., amlodipine and nifedipine. A 50-year-old man with essential hypertension was studied. Grapefruit juice (500 ml) was taken together with the antihypertensive drug, while one grapefruit was taken before drug ingestion. Blood pressures were measured using a digital automatic blood pressure monitor over a certain period. A single ingestion of grapefruit juice had no effect on plasma amlodipine concentration, but rapidly increased plasma nifedipine concentration and decreased blood pressure, while the effect on blood pressure was short-lasting. Grapefruit had no effect on either drug. It should be of concern that ingestion of a relatively large volume of grapefruit juice causes rapid decrease in blood pressure when the subject is treated by nifedipine.

Effect of Grapefruit Juice on the Pharmacokinetics of Nilotinib in Healthy Participants

Nilotinib (Tasigna; Novartis Pharmaceuticals) is a second-generation BCR-ABL tyrosine kinase inhibitor newly approved for the treatment of imatinib-resistant or imatinib-intolerant Philadelphia chromosome positive (Ph+) chronic myeloid leukemia in chronic phase or accelerated phase. This study evaluated the effect of grapefruit juice on the pharmacokinetics of nilotinib in 21 healthy male participants. All participants underwent 2 study periods during which they received a single oral dose of 400 mg nilotinib with 240 mL double-strength grapefruit juice or 240 mL water in a crossover fashion. Serial blood samples were collected for the determination of serum nilotinib concentrations by a validated liquid chromatography/tandem mass spectrometry assay. Concurrent intake of grapefruit juice increased the nilotinib peak concentration (C(max)) by 60% and the area under the serum concentration-time curve (AUC(0-infinity)) by 29% but did not affect the time to reach C(max) or the elimination half-life of nilotinib. The most common adverse events were headache and vomiting, which were mild or moderate in severity, and their frequency appeared to be similar between 2 treatments. Based on the currently available information about nilotinib and the observed extent of increase in nilotinib exposure, concurrent administration of nilotinib with grapefruit juice is not recommended.

Species Difference in the Effect of Grapefruit Juice on Intestinal Absorption of Talinolol between Human and Rat

Bioavailability of talinolol, a beta(1)-adrenergic receptor antagonist, was enhanced by coadministration with grapefruit juice (GFJ) in rats, whereas GFJ ingestion markedly reduced the absorption of talinolol in humans. Because our recent study indicated that the inhibitory effect of GFJ on organic anion-transporting polypeptide (Oatp)- and P-gp-mediated talinolol absorption depends on the concentration of naringin in ingested GFJ, the apparent inconsistent findings may be explained by the species difference in the affinity of naringin for OATP/Oatp and P-gp multidrug resistance 1 (MDR1/Mdr1) between humans and rats. Although human MDR1-mediated talinolol transport was not inhibited by 2000 microM naringin, naringin inhibited human OATP1A2-, rat Oatp1a5-, and rat Mdr1a-mediated talinolol transport with IC(50) values of 343, 12.7, and 604 microM, respectively, in LLC-PK1 cell and Xenopus laevis oocyte systems. Because the naringin concentration in commercially prepared GFJ was found to be approximately 1200 microM, these results suggested that GFJ would reduce the intestinal absorption of talinolol through inhibition of OATP1A2-mediated talinolol uptake in humans, whereas an increase of talinolol absorption is mainly through inhibition of Mdr1a-mediated efflux in rats. The rat intestinal permeability of talinolol measured by the in situ closed loop method was indeed significantly increased in the presence of GFJ, whereas a significant decrease was observed with 6-fold diluted GFJ, in which the naringin concentration was approximately 200 microM. The present study indicated that the species difference in the effect of GFJ on intestinal absorption of talinolol between humans and rats may be due to differences in the affinity of naringin for OATP/Oatp and MDR1/Mdr1 transporters between the two species.

Co-administration of grapefruit juice increases bioavailability of tacrolimus in liver transplant patients: a prospective study

The interactions between grapefruit juice (GFJ) and tacrolimus (FK506) metabolism remain obscure. The aim of this prospective study was to explore the effect of GFJ on the blood concentration of FK506 in liver transplant patients. Thirty liver transplant patients were enrolled in the study 1 month post-transplant and randomly divided into three equal-sized groups. Group A patients were treated with the standard FK506-based immunosuppressant regimen only and therefore served as the control; group B and C patients were treated with the standard FK506-based immunosuppressant regimen as well as one of two different kinds of GFJ, respectively. The blood concentrations of FK506 on the seventh day after GFJ intake were compared within each group and among groups. The dose of FK506 was adjusted depending on the valley concentration measured to a treatment window. The blood concentration of FK506 in both group B and group C patients was significantly enhanced, by 1.56 +/- 0.95 and 10.33 +/- 5.59 ng/ml, respectively, following the administration of GFJ for 1 week (compared with the concentration at the start of the experiment in each group; p < 0.05). However, at the end time point, the blood concentration of FK506 in group C patients was significantly increased (p < 0.05) relative to that of the control patients, while this was not the case in group B patients (p > 0.05). Group C patients could be treated with a smaller dose of FK506 (decreased by 2.3 +/- 1.3 mg/day for all patients; p = 0.011), amounting to a decrease in drug costs of approximately $8.70 +/- 5.60/day (p = 0.011). In the setting of a controlled clinical study, the co-administration of GFJ with FK506 increased the bioavailability of FK506. However, the concentration of tacrolimus should be closely monitored and the dose adjusted to the treatment window.

Dose–response relationship for the pharmacokinetic interaction of grapefruit juice with dextromethorphan investigated by human urinary metabolite profiles

Grapefruit juice (GFJ) has been shown to affect the pharmacokinetics of a large number of drugs, essentially by inhibition of efflux transporters and CYP3A4 monooxygenase in the small intestine. The GFJ dose usually used in human studies was one glass single-strength (1×). Information on a respective dose–response relationship is not available. We investigated the effect of GFJ of different concentration (0.25×, 0.5×, 1×, 2×) dosed in biweekly intervals in 19 volunteers. Components considered responsible for drug interactions, naringin, naringenin, bergamottin, and 6′,7′-dihydroxybergamottin were determined by LC–tandem mass spectrometry. Immediately after ingestion of GFJ, participants took an aqueous solution of dextromethorphan (DEX) as probe drug. Urine was collected in two sampling periods, 0–2 and 2–4 h, and excreted amounts of DEX and five metabolites associated with CYP3A4 and/or CYP2D6 enzyme activity were determined. Effects of GFJ were analyzed by the Wilcoxon matched-pairs signed-rank test against an average of four water control experiments. Two effects were highly significant: (i) a delay of total metabolite excretion in the first 2 h and (ii) an inhibition of the CYP3A4-dependent metabolic pathways. Effect magnitude and significance levels were dose-dependent and indicated 200 ml 1× GFJ as “lowest observed effect level” LOEL.

Toxicological and Pharmacokinetic Evaluation of Concomitant Intake of Grapefruit Juice and Simvastatin in Rats after Repeated Treatment over 28 Days

Since data concerning the toxicity and pharmacokinetics of concomitant repeated administration of grapefruit juice (GFJ) and simvastatin are lacking, we performed a chronic study in rats over a 4-week period using two different strengths (regular [RS] and double strength [DS]) of GFJ and two different doses of simvastatin (20 and 80 mg/kg, respectively). Both juices did not have a significant effect on the pharmacokinetic parameters of either simvastatin lactone (SVL) or its active metabolite simvastatin hydroxy acid (SVA) when administered concomitantly in a dose of 20 mg/kg over 28 days. However, when administered with 80 mg/kg simvastatin concentrations were elevated up to the last day of the study with DS-GFJ and to a lesser extent with RS-GFJ. Evaluation of toxicological parameters revealed a significant decrease in body and liver weights in groups receiving 20 mg/kg or 80 mg/kg simvastatin alone as well as in groups receiving simvastatin concomitantly with either DS- or RS-GFJ. No significant differences were detected for alanine (ALT) and aspartate (AST) aminotranferases in all groups. Chronic treatment with simvastatin significantly decreased plasma cholesterol levels (18 % for 20 mg/kg, 19 % for 80 mg/kg, respectively) as did coadministration of 80 mg/kg simvastatin with either RS-GFJ or DS-GFJ (33 %, 16 %). Interestingly, treatment with RS- or DS-GFJ alone significantly decreased plasma cholesterol levels by 22 % and 30 %, respectively. In conclusion, our results suggest that toxic effects in rats of concomitant intake of simvastatin and GFJ over 28 days are not more pronounced than those of simvastatin alone and that dose relationships between the administration of the juice and the drug may be important in determining the magnitude of the interaction.

Examining sex-related differences in enteric itraconazole metabolism in healthy adults using grapefruit juice

To explore whether sex-related differences in intestinal itraconazole metabolism exist in healthy adults using grapefruit juice (GFJ) as a selective enteric cytochrome P450 3A4 (CYP3A4) inhibitor. Twenty (ten female) subjects received 240 mL bottled water or single-strength GFJ from a frozen concentrate three times daily for 2 days. On day 3, the subjects received an itraconazole oral solution 200 mg with 240 mL of beverage followed 2 h later by 240 mL of the same beverage. Serial blood sampling for itraconazole and hydroxyitraconazole serum concentrations was performed over a 72-h period. After a 20-day washout, the subjects crossed over and repeated the study. Among the female subjects, GFJ reduced itraconazole weight-adjusted apparent oral clearance (Cl/F) (19%, p = 0.006) and increased AUC(0-infinity) (30%, p = 0.01), but produced no significant change in hydroxyitraconazole pharmacokinetics. In males, GFJ produced no significant change in either itraconazole, or hydroxyitraconazole pharmacokinetics. Grapefruit juice also significantly reduced the metabolite:parent AUC(0-infinity) ratio (12%, p = 0.047), in females, but not males. Itraconazole weight-adjusted oral Cl/F was significantly higher in females than males when itraconazole was administered with water (56%, p = 0.009), and although the extent to which GFJ altered itraconazole weight-adjusted oral CL/F was greater in females, it did not differ significantly between the sexes (p = 0.085). The influence of GFJ on the presystemic metabolism of itraconazole was greater in females than males. Repeated ingestion of GFJ significantly reduced itraconazole weight-adjusted oral CL/F and significantly increased exposure in females, but it produced no significant change among males. Although itraconazole weight-adjusted oral Cl/F was much higher in females than in males, the extent to which GFJ altered itraconazole weight-adjusted oral CL/F did not differ significantly between the sexes.

Relationship between Lipophilicities of 1,4-Dihydropyridine Derivatives and Pharmacokinetic Interaction Strengths with Grapefruit Juice

It is well known fact that the strengths of drug interactions with grapefruit juice (GFJ) differ greatly depending on the 1,4-dihydropyridine calcium channel antagonist (DHP) used. However, there are no available data on the relationship between interactions with GFJ and its physicochemical attributes. Therefore we endeavored to study the correlation between calculated logP values, indicating lipophilicity, from chemical structures of DHPs as well as water diffusion, molecular volume, molecular polarization, molecular density, refractive index, topologic polar surface area, and calculated molar refractivity. Thirteen forms of DHP, amlodipine, azelnidipine, benidipine, cilnidipine, efonidipine, felodipine, manidipine, nicardipine, nifedipine, nimodipine, nisoldipine, nitrendipine, and pranidipine were analyzed due to clinical trials performed with GFJ and these agents. The pharmacokinetic interaction strengths were defined in common logarithmic values of increasing ratios of area under the plasma concentration-time curve (AUC) with GFJ intake compared with controls. Physicochemical properties including three categories of predicted logP values were calculated from the structures of DHPs and their estimated relationship with the interactions. As a result, the logP values indicated significant positive correlations with the interaction strengths. This finding suggests that lipophilicity is an important factor in the strengths of pharmacokinetic interactions of DHPs with GFJ intake.

Enhancement by Grapefruit Juice of Morphine Antinociception

The aim of this study was to investigate the effect of grapefruit juice intake on the antinociception of morphine in rats. The antinociception of morphine (30 mg/kg, per os (p.o.)) was significantly enhanced by the oral administration of grapefruit juice (2 ml/rat). Further, the effect of grapefruit juice was examined in morphine-tolerant rats. The repeated administration of morphine (100 mg/kg p.o.) for 5 d caused a marked decrease in the antinociception, indicating the development of morphine-tolerance. In the morphine-tolerant rats, oral administration of grapefruit juice potentiated significantly the antinociceptive effect of morphine. To examine the pharmacokinetics of morphine after the repeated treatment with morphine for 5 d, microdialysis probes were implanted into the jugular vein and spinal intrathecal space in rats. The morphine concentrations in the blood and intrathecal cerebrospinal fluid (CSF) were gradually decreased by the repeated treatment with morphine. The grapefruit juice treatment significantly increased the blood concentration of morphine in morphine-tolerant rats. These results suggest that oral administration of grapefruit juice enhances the morphine antinociception by increasing the intestinal absorption of this agent.

A prospective study of grapefruit and grapefruit juice intake and breast cancer risk

Sir, In a recent interesting study by Monroe et al (2007), grapefruit intake was associated with an increase in breast cancer risk, and they hypothesised that this might be mediated by an effect on endogenous oestrogen levels. However, the researchers were unable to examine grapefruit juice intake. Therefore, we examined grapefruit and grapefruit juice intake and breast cancer risk in the Nurses' Health Study. Briefly, the Nurses' Health Study is a prospective cohort consisting of women aged 30–55 years in 1976 (Kim et al 2006). Medical and lifestyle information was obtained with general follow-up questionnaires every 2 years and with semi quantitative food frequency questionnaires that included intakes of grapefruit and grapefruit juice in 1984, 1986, 1990, 1994, and 1998. In both age-adjusted (not shown) and multivariate analyses adjusted for standard breast cancer risk factors, we found no overall association with either grapefruit or grapefruit juice intake and breast cancer risk among all women in the cohort, and among postmenopausal women only (Table 1). Furthermore, our results did not change once additional covariates – alcohol, saturated fat, dietary fibre, and soluble fibre – included by Monroe et al were added to our models. Table 1 Multivariate relative risks of breast cancer incidence between 1984 and 2002 by cumulatively averaged grapefruit and grapefruit juice intake Stratification by BMI did not alter the breast cancer risk with either grapefruit or grapefruit juice intake. However, stratification by hormone therapy showed a significant decrease in risk of breast cancer with greater intake of grapefruit in women who never used hormone therapy (multivariate RR comparing ¼ grapefruit or more per day to none=0.78, 95% CI, 0.59–1.04, P trend=0.03). This is contrary to the findings of Monroe et al, who observed a significant increase in risk of breast cancer with greater consumption of grapefruit in this subgroup. Furthermore, the association between grapefruit (not grapefruit juice) intake and breast cancer risk differed significantly by oestrogen and progesterone receptor status of the tumours. No association was observed in women with oestrogen and progesterone receptor positive cancers. However, in women with oestrogen and progesterone receptor negative cancers, there was a significant decrease in breast cancer risk with increased consumption of grapefruit (multivariate RR comparing ¼ grapefruit or more per day to none=0.60, 95% CI, 0.37–0.98, P trend=0.03). We also examined cross-sectionally the relationship between consumption of grapefruit and grapefruit juice and plasma levels of oestrogens among 701 postmenopausal women not using hormone replacement. No significant correlation was observed (grapefruit, grapefruit juice) for plasma oestradiol (r=0.02, −0.04), oestrone (r=0.00, −0.02), or oestrone sulphate (0.09, 0.01). Our findings do not support an adverse effect of consumption of grapefruit or grapefruit juice on risk of breast cancer or on endogenous hormone levels.

Possible case of potentiation of the antiplatelet effect of cilostazol by grapefruit juice

We present a case of purpura associated with concomitant ingestion of cilostazol, aspirin and grapefruit juice. A 79-year-old man with atherosclerosis obliterans, taking cilostazol and aspirin, complained of purpura. Interview by a pharmacist revealed that he had been taking grapefruit juice for a month. His purpura disappeared upon cessation of grapefruit juice, although his medication was not altered. The most probable cause of his purpura is an increase in the blood level of cilostazol because of the inhibition of cilostazol metabolism by components of grapefruit juice. Aspirin may possibly have potentiated the risk of purpura. Grapefruit juice should be avoided in patients taking cilostazol, especially in patients being concomitantly treated with other anticoagulants.

Intestinal Drug Transporter Expression and the Impact of Grapefruit Juice in Humans

The goals of this study were to assess the extent of human intestinal drug transporter expression, determine the subcellular localization of the drug uptake transporter OATP1A2, and then to assess the effect of grapefruit juice consumption on OATP1A2 expression relative to cytochrome P450 3A4 and MDR1. Expression of drug uptake and efflux transporters was assessed using human duodenal biopsy samples. Fexofenadine uptake by different transporters was measured in a transporter-transfected cell line. We investigated the influence of grapefruit juice on pharmacokinetics of orally administered fexofenadine. The effect of grapefruit juice on the expression of intestinal transporters was determined using real-time polymerase chain reaction and Western blot analysis. In the duodenum of healthy volunteers, an array of CYP enzymes as well as uptake and efflux transporters was expressed. Importantly, uptake transporters thought to be liver-specific, such as OATP1B1 and 1B3, as well as OATP2B1 and 1A2 were expressed in the intestine. However, among OATP transporters, only OATP1A2 was capable of fexofenadine uptake when assessed in vitro. OATP1A2 colocalized with MDR1 to the brush border domain of enterocytes. Consumption of grapefruit juice concomitantly or 2 h before fexofenadine administration was associated with reduced oral fexofenadine plasma exposure, whereas intestinal expression of either OATP1A2 or MDR1 remained unaffected. In conclusion, an array of drug uptake and efflux transporters are expressed in the human intestine. OATP1A2 is likely the key intestinal uptake transporter for fexofenadine absorption whose inhibition results in the grapefruit juice effect. Although short-term grapefruit juice ingestion was associated with reduced fexofenadine availability, OATP1A2 or MDR1 expression was unaffected.

Arzneimittelspiegel als pharmakotherapeutisches Werkzeug bei der Behandlung mit Psychopharmaka

Therapeutic drug monitoring (TDM) is used increasingly for managing psychiatric outpatients, where the preanalytic error risk is high. Blood samples must be collected under steady-state conditions immediately before ingestion of the morning dose or before the next injection. In order to interpret the plasma levels accurately, age, gender, ethnicity, compliance, drug dosage, renal and hepatic function and comedication incl. smoking habits and diet (esp. caffeine intake and consumption of grapefruit juice) have to be taken into account. If in doubt, aberrant plasma levels should be confirmed by a second control under optimized conditions. Pharmacogenetic testing enables the identification of abnormal metabolizers. TDM and pharmacogenetic tests are useful tools to improve pharmacotherapy by preventing dose-dependent adverse drug events, optimizing dosage during long-term treatment and identifying ultrarapid metabolizers and malcompliance.