Grapefruit Juice Research Articles

Tacrolimus and herbs interactions: a review.

The calcineurin inhibitor tacrolimus (TAC) shows inter-and intra-individual variability in blood levels and has a narrow therapeutic index. To reduce the chance of fluctuations in immunosuppressive activity and potential drug interactions, it is critical to keep track of drug concentrations. Cytochrome-P450 (CYP) isoenzymes CYP3A4 and CYP3A5, as well P-glycoprotein (P-gp) are involved in TAC bioavailability. TAC's interactions with herbal extracts are reviewed here, because with more people using TAC, it is becoming crucial to know which extracts, which are often part of self-medication, can alter TAC blood concentrations. TAC bioavailability was decreased when co-administered with St John's wort (SJW), cranberry, rooibos tea, and boldo in human models by induction of the CYP450 system and/or P-gp efflux pump, meanwhile, the TAC bioavailability was increased when co-administered with grapefruit juice (GFJ), schisandra, berberine, turmeric, pomegranate juice, pomelo, and ginger in human and or animal models by inhibition effect on CYP450 system and/or P-gp efflux pump. Thus, physicians and pharmacists should thoroughly educate their patients regarding the use of supplemental herbs before administering TAC. Furthermore, patients who are already undergoing TAC treatment should be informed about the possibility of dangerous interactions between herbal remedies and TAC.

Analyzing Potential Intestinal Transporter Drug-Drug Interactions: Reevaluating Ticagrelor Interaction Studies

Previous studies evaluating ticagrelor drug-drug interactions have not differentiated intestinal versus systemic mechanisms, which we do here. Using recently published methodologies from our laboratory to differentiate metabolic- from transporter-mediated drug-drug interactions, a critical evaluation of five published ticagrelor drug-drug interactions was carried out to investigate the purported clinical significance of enzymes and transporters in ticagrelor disposition. The suggested CYP3A4 inhibitors, ketoconazole and diltiazem, displayed unchanged mean absorption time (MAT) and time of maximum concentration (Tmax) values as was expected, i.e., the interactions were mainly mediated by metabolic enzymes. The potential CYP3A4/P-gp inhibitor cyclosporine also showed an unchanged MAT value. Further analysis assuming there was no P-gp effect suggested that the increased AUC and unchanged t1/2 for ticagrelor after cyclosporine administration were attributed to the inhibition of intestinal CYP3A4 rather than P-gp. Rifampin, an inducer of CYP3As after multiple dosing, unexpectedly showed decreased MAT and Tmax values, which cannot be completely explained. In contrast, grapefruit juice, an intestinal CYP3A/P-gp/OATP inhibitor, significantly increased MAT and Tmax values for ticagrelor, which may be due to activation of P-gp or inhibition of OATPs expressed in intestine. This study provides new insight into the role of transporter pathways in ticagrelor intestinal absorption by examining potential MAT and Tmax changes mediated by drug-drug interactions.

Bergamottin a CYP3A inhibitor found in grapefruit juice inhibits prostate cancer cell growth by downregulating androgen receptor signaling and promoting G0/G1 cell cycle block and apoptosis.

Prostate cancer is the second leading cause of cancer related death in American men. Several therapies have been developed to treat advanced prostate cancer, but these therapies often have severe side effects. To improve the outcome with fewer side effects we focused on the furanocoumarin bergamottin, a natural product found in grapefruit juice and a potent CYP3A inhibitor. Our recent studies have shown that CYP3A5 inhibition can block androgen receptor (AR) signaling, critical for prostate cancer growth. We observed that bergamottin reduces prostate cancer (PC) cell growth by decreasing both total and nuclear AR (AR activation) reducing downstream AR signaling. Bergamottin’s role in reducing AR activation was confirmed by confocal microscopy studies and reduction in prostate specific antigen (PSA) levels, which is a marker for prostate cancer. Further studies revealed that bergamottin promotes cell cycle block and accumulates G0/G1 cells. The cell cycle block was accompanied with reduction in cyclin D, cyclin B, CDK4, P-cdc2 (Y15) and P-wee1 (S642). We also observed that bergamottin triggers apoptosis in prostate cancer cell lines as evident by TUNEL staining and PARP cleavage. Our data suggests that bergamottin may suppress prostate cancer growth, especially in African American (AA) patients carrying wild type CYP3A5 often presenting aggressive disease.

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.

Analysis and Potential Value of Compounds Extracted From Star Ruby, Rio Red, and Ruby Red Grapefruit, and Grapefruit Juice Processing Residues via Steam Explosion.

Culled whole grapefruit (WG) and grapefruit juice processing residues (GP) are currently incorporated into low-cost animal feed. If individual chemical components found within these side streams could be recovered as high-value coproducts, this would improve the overall value of the grapefruit crop. In this study, pectic hydrocolloids, sugars, volatiles, phenolics, and flavonoids were extracted from Star Ruby, Rio Red, and Ruby Red GP and WG using a continuous pilot scale steam explosion system. Up to 97% of grapefruit juice oils and peel oils could be volatilized and contained 87–94% d-limonene. The recovery of pectin, as determined by galacturonic acid content, was between 2.06 and 2.72 g 100 g−1. Of the phenolics and flavonoids analyzed in this study, narirutin and naringin were extracted in the amounts of up to 10,000 and 67,000 μg g−1, respectively.

Marination with citric acid, lemon, and grapefruit affects the sensory, textural, and microstructure characteristics of poultry meat

ABSTRACT 1. This study aimed to determine the effects of marination liquids prepared with citric acid (CA-0.5%), lemon (LJ-100%) and grapefruit (GJ-100%) juices on the pH, colour (L*, a*, b*, Chroma, hue angle, total colour differences), cooking loss (CL), water holding capacity (WHC) and marinade absorption (MA) of chicken breast meat. Textural, microstructure (scanning electron microscopy (SEM), confocal laser scanning microscopy (CLSM)) and sensory properties were investigated. 2. As a result of marination, there was a significant (P < 0.01) decrease in the CL and pH values and an increase in WHC and MA values of marinated meat. The L*, b* and chroma values of chicken breast meats marinated with all marinades increased significantly (P < 0.01). 3. While CLSM showed that LJ gave rise to a partial deterioration in muscle fibres, SEM indicated that LJ had irregular muscle fibres, some fibres were broken and separated from each other. The lowest hardness value was established in the LJ group from texture analysis. In the sensory analysis, marinated samples generally received higher scores from panellists compared with the control.

Novel Bruton's Tyrosine Kinase inhibitor remibrutinib: Drug-drug interaction potential as a victim of CYP3A4 inhibitors based on clinical data and PBPK modeling.

Remibrutinib, a novel oral Bruton’s Tyrosine Kinase inhibitor (BTKi) is highly selective for BTK, potentially mitigating the side effects of other BTKis. Enzyme phenotyping identified CYP3A4 to be the predominant elimination pathway of remibrutinib. The impact of concomitant treatment with CYP3A4 inhibitors, grapefruit juice and ritonavir (RTV), was investigated in this study in combination with an intravenous microtracer approach. Pharmacokinetic (PK) parameters, including the fraction absorbed, the fractions escaping intestinal and hepatic first‐pass metabolism, the absolute bioavailability, systemic clearance, volume of distribution at steady‐state, and the fraction metabolized via CYP3A4 were evaluated. Oral remibrutinib exposure increased in the presence of RTV 4.27‐fold, suggesting that remibrutinib is not a sensitive CYP3A4 substrate. The rich PK dataset supported the building of a robust physiologically‐based pharmacokinetic (PBPK) model, which well‐described the therapeutic dose range of 25–100 mg. Simulations of untested scenarios revealed an absence of drug‐drug interaction (DDI) risk between remibrutinib and the weak CYP3A4 inhibitor fluvoxamine (area under the concentration‐time curve ratio [AUCR] <1.25), and a moderate effect with the CYP3A4 inhibitor erythromycin (AUCR: 2.71). Predictions with the moderate and strong CYP3A4 inducers efavirenz and rifampicin, suggested a distinct remibrutinib exposure decrease of 64% and 89%. Oral bioavailability of remibrutinib was 34%. The inclusion of an intravenous microtracer allowed the determination of all relevant remibrutinib PK parameters, which facilitated construction of the PBPK model. This will provide guidance on the selection or restriction of comedications and prediction of DDI risks.

Comprehensive identification and distribution pattern of 37 oxygenated heterocyclic compounds in commercially important citrus juices

Oxygenated heterocyclic compounds (OHCs) are among the most biologically active components in citrus fruits which exert health benefits but also involve juice-drug interactions. However, current knowledge of OHC distribution in citrus juices is incomplete. By analyzing 173 samples from orange, mandarin, grapefruit, pomelo, lemon, and lime juices, this study constructed a comprehensive OHC (10 methoxyflavones, 12 coumarins, 15 furanocoumarins) compositional pattern of the six commercially important species. OHCs were determined using a newly developed high-resolution HPLC separation with UV and fluorescence detection. Identifications were based on matching an innovative combination of full UV and fluorescence spectra, multiwavelength fluorescence emission peak ratios, and alkyl aryl ketone retention index values with those of standards. Forty-six previously unreported OHC occurrences (12 methoxyflavones, 27 coumarins and 9 furanocoumarins) were identified in the six juice-species. Unique OHC markers were identified in mandarin (5-demethyltangeretin), pomelo (meranzin), and lime (heraclenol) juices. Orange and mandarin juices are characterized by two and five methoxyflavones respectively; pomelo and grapefruit by 5-substituted furanocoumarins and 7,8-disubstituted coumarins; lemon and lime by byakangelicin, 8-geranyloxypsoralen, and 5-geranoxy-7-methoxycoumarin. The greatly expanded and detailed OHC distribution pattern provides additional information for future epidemiological work investigating the relationships between citrus juice OHCs intake and health outcomes.

Preparation of Aspergillus niger 426 naringinases for debittering citrus juice utilization of agro-industrial residues.

Naringin, considered as the main bitter component of grapefruit, requires the use of enzymes to reduce the level of this substance during juice processing. For this reason, it has been the focus of many studies. In this study, to increase the production of naringinase by Aspergillus niger cultivated in solid-state fermentation (SSF), a three-component simplex-centric mixing design along with a response surface methodology (RSM) was applied to generate statistical models and analyze the dataset. First, grapefruit peel, rice bran, and wheat bran were used for substrate selection for naringinase production and, finally, selected the best of the three inducers or their mixtures to remove the bitterness of grapefruit juice. Cultivation with 2.3g of grapefruit peel, 2.5g of rice bran, and 5.2g of wheat bran and medium supplementation with a mixture of naringin, rutin, and hesperidin in the concentration of 2, 5, 4.5, and 3.0g/L, respectively, resulted in a maximum activity of 28 U/mL. The results indicate that the sequencing procedure, which allowed the definition of an optimal mixture of components, is a new way for microorganisms to have a high naringinase yield, in particular by SSF, since our data showed a 96% increase in the production of naringinase. This dataset can help other researchers apply a mixing design to increase enzyme production.

Does Responsiveness to Basic Tastes Influence Preadolescents' Food Liking? Investigating Taste Responsiveness Segment on Bitter-Sour-Sweet and Salty-Umami Model Food Samples.

The objective of this study was to investigate the relationships between taste responsiveness and food liking in preadolescents. Model food samples of grapefruit juice (GF) and vegetable broth (VB) modified with four additions of sucrose and sodium chloride, respectively, were employed. Intensity perception for sweetness, sourness, and bitterness were measured in GF while saltiness and umami were measured in VB. The children (N = 148) also completed food choice, familiarity, stated liking and neophobia questionnaires. The test was conducted at school, with instructions provided remotely via video call. Four segments were defined differing in basic taste responsiveness. Segments and sucrose concentrations significantly affected liking for GF, while no significant effect of segments and sodium chloride concentrations occurred on liking for VB. An increasing sucrose concentration was positively associated with liking for GF only in the segment with low responsiveness to bitter and sour tastes. No significant differences across segments were found for food choice, familiarity, stated liking, and neophobia. Conclusively, relationships between taste responsiveness and liking are product and basic taste-dependent in addition to being subject-dependent. Strategies to improve acceptance by using sucrose as a suppressor for warning sensations of bitterness and sourness can be more or less effective depending on individual responsiveness to the basic tastes.

Immobilization of naringinase on asymmetric organic membranes: Application for debittering of grapefruit juice

An enzymatic membrane reactor (EMR) is assembled for the immobilization of naringinase on a polyethersulfone ultrafiltration membrane, based on fouling-induced method. The effects of molecular weight cut-off, membrane configuration, applied pressure, enzyme concentration and pH are studied in terms of permeate rate, immobilization efficiency, and biocatalytic conversion. The 10 kDa membrane operating in reverse mode, 0.2 MPa, 0.3 gL−1 of enzyme in acetate buffer at pH 5 and cross-linking with 0.25% glutaraldehyde showed the highest naringin conversion (73%). It was determined that the intermediate pore blocking model was the predominant fouling mechanism for the enzymatic immobilization. The EMR was applied for debittering of grapefruit juice, achieving a conversion of naringin below bitterness threshold and maintaining the antioxidant capacity of the juice. Furthermore, the biocatalytic activity of immobilized enzyme was retained at a high level at least during three consecutive reaction runs, with overnight storage at 4 °C after each run. Industrial relevanceThe potential of membrane technologies in the juice industries is widely recognized today. The development of EMR with naringinase activity is an attractive option for reducing bitterness that could replace current techniques, due to its high specificity and effectiveness, possibility of repeated and continuous use, and in order to retain the properties of juice as much as possible. The research therefore represents an advance in the application of biocatalytic membranes as technological alternative for juice debittering.

Green Synthesis of SnO2/Carbon Quantum Dots Nanocomposite for Gas Sensing Application

SnO2/Carbon Quantum Dots (CQDs) were synthesized by a hydrothermal method using grape fruit juice. The nanocomposites (NC) were characterized by means of XRD and Gas sensing properties. The sensor devices were fabricated using SnO2/CQDs NC as sensing materials. The effect of the CQDs content on the gas-sensing responses and the gas-sensing selectivity was investigated. In this work, the gas sensor developed is exposed to carbon monoxide polluting gas like at different temperatures to determine the optimum operating temperatures which allow obtaining the highest sensitivity for gas. Keywords: Green synthesis, Grape fruit, SnO2 nanoparticles, CQDs, Gas sensor.

Complementary and Alternative Medicine Use in First-time and Recurrent Kidney Stone Formers

To describe the patterns of complementary and alternative medicine (CAM) among patients with kidney stones and analyze the alkali content of commonly used CAM therapies. We prospectively conducted structured interviews with patients who presented to a specialty stone clinic for the management of kidney stones. Open-ended questions were used to elicit information regarding CAM knowledge, formulation/dosing, and patterns of use. Several common CAM therapies were then analyzed for their alkali, organic anion, and sugar content. Of 103 subjects, 82 (80%) patients reported knowledge of CAM and 52 (50%) reported using CAM. Patients with recurrent kidney stones were more likely to report using CAM than patients with first-time episodes (56% vs 26%, P = 0.04). Some respondents reported their condition decreased in severity or frequency since starting CAM therapy (17%) and improvements in pain (12%). Total alkali content per serving of the tested supplements was 0 mEq (Stonebreaker), 1.5 mEq (Ocean Spray Cranberry Juice Cocktail), 4.7 mEq (Lakewood Pure Cranberry Juice), 0.6 mEq (Braggs Apple Cider Vinegar), 11.9 mEq (LithoBalance), 9.5 mEq (Simply Grapefruit Juice), 19.8 mEq (KSP-Key Lime), and 20.2 mEq (KSP-Very Berry). Patients with kidney stones may use CAM to alleviate symptoms or prevent recurrence. Commercially available CAM therapies may contain comparable alkali content to commonly prescribed citrate therapy. These data suggest that providers should be prepared to discuss the role of CAM with their patients.

Investigation of the impact of grapefruit juice, pomegranate juice and tomato juice on pharmacokinetics of brexpiprazole in rats using UHPLC-QTOF-MS.

Brexpiprazole (BRX) is approved for the treatment of schizophrenia and major depressive disorders and it is mainly metabolized by CYP3A4 and CYP2D6. Grapefruit juice (GFJ), pomegranate juice (PJ) and tomato juice (TJ) have the potential to inhibit CYP3A4 enzymes in the body. However, fruit juice-drug interactions between BRX and GFJ, PJ and TJ have not been studied extensively. The present study describes the influence of GFJ, PJ and TJ on the pharmacokinetic parameters of BRX in rats. The study samples were analyzed using a mass-accurate and single-step bioanalytical method by ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry over a wide calibration range of 20-1,500 ng/ml. The results of the pharmacokinetic study denoted that the combined administration of GFJ and PJ could increase systemic exposure of BRX. The area under the curve of BRX increased 3.43- and 1.88-fold with co-administration of GFJ and PJ, respectively, while TJ with BRX had no effect on the area under the curve. Time to peak concentration and half-life were not significantly changed by any juice co-administration. The results show that GFJ and PJ affect the pharmacokinetic profile of BRX and hence advice needs to be given to patients.

CYP3A-Mediated Drug Interaction Profile of Bruton Tyrosine Kinase Inhibitor, Acalabrutinib

▪Background:Acalabrutinib (ACP-196) is a highly selective, potent, covalent inhibitor of Bruton tyrosine kinase (BTK), in development for the treatment of hematologic malignancies. Acalabrutinib has rapid absorption and a short pharmacokinetic (PK) half-life; twice daily dosing resulted in near complete and continuous BTK inhibition in patients with chronic lymphocytic leukemia (CLL) (Byrd JC, et al. 2016).CYP3A-mediated oxidation is the primary route of elimination for the marketed BTK inhibitor, ibrutinib (de Zwart et al., 2016). Coadministration of ibrutinib with ketoconazole (a strong CYP3A inhibitor) increased dose-normalized maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) by 29- and 24-fold, respectively, whereas coadministration of rifampin (a strong CYP3A inducer) decreased Cmax and AUC of ibrutinib by more than 13- and 10-fold, respectively (IMBRUVICA® (ibrutinib) package insert 2017). Grapefruit juice, which is known to contain CYP3A inhibitors, resulted in a 3.6- and 2.1-fold increase in Cmax and AUC of ibrutinib, respectively (de Jong J. et al., 2015).To evaluate the effects of CYP3A inhibitors and inducers on the PK profile, safety and tolerability of acalabrutinib, administered alone and coadministered with itraconazole, rifampin, or grapefruit juice, three CYP3A-related drug-drug interaction (DDI) studies were performed in healthy subjects.Methods:DDI study 1: Strong CYP3A inhibitor: Subjects (N=18) received 50 mg acalabrutinib alone and with the last dose of a 200 mg twice daily, 11-dose itraconazole regimen.DDI study 2: Strong CYP3A inducer: Subjects (N=24) received 100 mg acalabrutinib alone and with the first and last dose of a 600 mg daily, 9-dose rifampin regimen.DDI study 3: Grapefruit juice-CYP3A inhibitor: Subjects (N=12) received 100 mg acalabrutinib. Grapefruit juice (240 mL) was given twice, 12 hours before and with the 100 mg acalabrutinib dose.In all studies, plasma PK and geometric mean ratio (GMR) (90% CI) of acalabrutinib Cmax and AUC were evaluated, along with PK of concomitant itraconazole and rifampin.Results:In the presence of steady-state itraconazole, geometric mean (GM) acalabrutinib AUC and Cmax increased by 5.1-fold (90%CI 4.5-5.8) and 3.9-fold (3.2-4.7), respectively, relative to acalabrutinib given alone.In the presence of steady-state rifampin, acalabrutinib AUC decreased by 4.3-fold (GMR 0.23 [90%CI 0.19-0.29]), relative to acalabrutinib given alone. Cmax decreased by 3.1-fold (GMR 0.32 (90%CI 0.24-0.42)), relative to acalabrutinib given alone.In the presence of grapefruit juice, acalabrutinib AUC decreased by 1.2-fold (GMR 0.83 [90%CI 0.72-0.97]) relative to acalabrutinib given alone. Cmax decreased by 1.5-fold (GMR 0.65 [90%CI 0.45-0.93]) relative to acalabrutinib given alone.Overall, acalabrutinib was safe and well tolerated by the healthy subjects in these studies, when administered alone or when coadministered with itraconazole, rifampin, or grapefruit juice.Conclusions:In healthy subjects, coadministration of strong CYP3A inhibitor, itraconazole, increased acalabrutinib AUC by 5.1-fold and strong CYP3A inducer, rifampin, decreased acalabrutinib AUC by 4.3-fold. Grapefruit juice resulted in a 1.2-fold decrease in acalabrutinib AUC. DisclosuresIzumi:Acerta Pharma: Employment, Equity Ownership. Pearson:Acerta Pharma: Consultancy; Pearson Pharma Partners: Consultancy. Hamdy:Acerta Pharma: Employment, Equity Ownership, Patents & Royalties: Acalabrutinib related patents. Rodriquez:Acerta Pharma: Employment. Yang:Acerta Pharma: Employment, Equity Ownership. Ulrich:Acerta Pharma BV: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: EP3076974 A1 Therapeutic combination of a pi3k inhibitor and a btk inhibitor. No royalties.. Podoll:Acerta Pharma: Employment; Astra Zeneca: Equity Ownership. Andrew:Acerta Pharma: Employment; Astra Zeneca: Equity Ownership. Krejsa:Acerta Pharma: Employment, Equity Ownership; Astra Zeneca: Equity Ownership. Ingallinera:Astra Zeneca: Equity Ownership; Acerta Pharma: Employment, Equity Ownership. Slatter:Acerta Pharma: Employment; Astra Zeneca: Equity Ownership.

Natural synthesis of silver nanoparticles from grape fruit juice and estimation of antimicrobial activity

Silver has been known for its antimicrobial activity for a very long time. Formulation of silver particles that range from 1-100nm in size makes it even more potent to induce antimicrobial effect. Green chemistry has started to become more frequent in the field of biochemical research. Silver nanoparticles synthesized from green synthesis method provide a cheap and environmental friendly method of nanoparticle preparation. The aim of the current study is green synthesis of silver nanoparticles using tomato juice as reducing and capping agent and evaluation of its antimicrobial activity. The stability and conformation of SNPs was determined by UV-visible spectroscopy. The antimicrobial activity of synthesized SNPs was determined against E.coli DH5α. Ultraviolet spectroscopic analysis offered peak at 400 nm that indicate the production of SNPs of adequate size. E.coli DH5α showed considerable decrease upon introduction of SNPs to the bacterial inoculum. Upon increasing the concentration of silver nanoparticles an increase in zone of inhibition was recorded. For 70µg/ml of SNPs, the zone of inhibition was 0.5 cm, while 0.6 cm, 0.7 cm and 0.7cm was recorded for 100µg/ml, 150µg/ml and 200µg/ml of SNPs respectively. The efficacy of antimicrobial activity of SNPs derived from tomato juice proves its potential use in pharmaceutical and medicinal industries for synthesis of nanomedicine.

Effects of Citri Reticulatae Pericarpium and grapefruit juice on the pharmacokinetics of omeprazole in rats.

The effects of Citri Reticulatae Pericarpium (CRP) and grapefruit juice (GFJ) on the pharmacokinetics of omeprazole were investigated in this study. Sprague-Dawley rats were pretreated with CRP decoction or GFJ for 28 consecutive days. After a single intragastric administration of 6.0mg/kg, the concentration of omeprazole in the plasma was determined by high-performance liquid chromatography (HPLC), and the pharmacokinetic parameters were calculated by Kinetica software 5.0. A high-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (HPLC-Q-TOF-MS) method was established to identify the chemical components in CRP decoction and GFJ. The results showed that the AUCt-∞ was significantly increased when coadministrated with CRP. The AUC0-t and AUC0-∞ was remarkably increased; the Cl was decreased when coadministrated with GFJ. A total of 31 and 28 bioactive compounds were identified in the CRP decoction and GFJ, respectively. Flavonoids and furanocoumarins, including hesperidin, hesperetin, naringenin, sinensetin, tangeretin, nobiletin, and 6',7'-dihydroxybergamottin, were simultaneously identified in CRP decoction and GFJ. This study indicates that the increased bioavailability of omeprazole may be due to the inhibition of hepatic cytochrome P450 enzymes, and the systemic exposure should be monitored when concomitant administration with CRP and GFJ. PRACTICAL APPLICATIONS: Citri Reticulatae Pericarpium (CRP) has been widely consumed as a daily condiment, functional food, and a traditional Chinese medicine. Omeprazole, primary metabolized by CYP450 enzymes, was usually coadministered with CRP for the treatment of gastrointestinal disease. Studies have confirmed that much fruit juices, including grapefruit juice, may affect drug metabolism enzymes. CRP and grapefruit (Citrus paradisi Macf.) belong to the genus Citrus and family Rutaceae with different species. Therefore, the pharmacokinetic interaction of CRP decoction and grapefruit juice with omeprazole is worthy of attention. The results of this study can provide basic pharmacological data support for the safe and effective clinical use of omeprazole. It can also provide a theoretical basis for the development of new functional products and daily application of CRP.

A narrative review of the importance of pharmacokinetics and drug-drug interactions of preventive therapies in migraine management.

ObjectiveTo review the pharmacokinetics of major classes of migraine preventives and the clinical implications of drug–drug interactions (DDIs) with the use of these therapies in migraine management.BackgroundPreventive treatments for migraine are recommended for a large proportion of patients with frequent migraine attacks. These patients often exhibit a number of comorbidities, which may lead to the introduction of multiple concomitant therapies. Potential DDIs must be considered when using polytherapy to avoid increased risk of adverse events (AEs) or inadequate treatment of comorbid conditions.MethodsA literature search was performed to identify pharmacokinetic properties and potential DDIs of beta‐blockers, antiepileptic drugs, antidepressants, calcium channel blockers, gepants, and monoclonal antibody therapies targeting the calcitonin gene‐related peptide pathway with medications that may be used for comorbid conditions.ResultsMost DDIs occur through alterations in cytochrome P450 isoenzyme activity and may be complicated by genetic polymorphism for metabolic enzymes. Additionally, drug metabolism may be altered by grapefruit juice ingestion and smoking. The use of migraine preventive therapies may exacerbate symptoms of comorbid conditions or increase the risk of AEs associated with comorbid conditions as a result of DDIs.ConclusionsDDIs are important to consider in patients with migraine who use multiple medications. The development of migraine‐specific evidence‐based preventive treatments allows for tailored clinical management that reduces the risk of DDIs and associated AEs in patients with comorbidities.

In vitro dissolution characteristics of patent, generic and similar brands of naproxen in various dissolution media

Purpose: To investigate the dissolution properties of various brands of naproxen in four dissolution media in order to forecast their biological availability.&#x0D; Methods: Dissolution tests were carried out in a dissolution tester with 48 tablets of different naproxen brands in 900 mL of 0.1 M phosphate buffer, pH 7.4. Subsequently, the medium was modified with 600 mL of buffer plus 300 mL of cola drink, grapefruit or milk. Each sample was taken and brought to a concentration approximating that of a reference solution. Absorbance at 332 nm was determined and the dissolution, Q, was calculated (Q values ≥ 80.0 ± 5 % were acceptable).&#x0D; Results: Dissolution in buffer was &gt; 85 %. In cola drink, it was &lt; 80 %, while in grapefruit juice, it was in the range of 7 - 68 %. Using 2-way ANOVA, these media and the three naproxen brands showed significant differences (F = 68.90, p = 0.0000; F = 23.18, p = 0.0000). With Fisher's LSD test, two of these media contributed consistently to dissolution, and the three drug brands showed statistically different dissolution profiles (p ≤ 0.05).&#x0D; Conclusion: Caution must be exercised cola drink, grapefruit juice and milk are used to administered naproxen as the biological availability of the drug may be altered.

Intestinal Absorption of Alogliptin Is Mediated by a Fruit-Juice-Sensitive Transporter.

Alogliptin (ALG), an inhibitor of dipeptidylpeptidase-4, is used in the management of type 2 diabetes mellitus, and has a high absorption rate (>60-71%), despite its low lipophilicity (logP=-1.4). Here, we aimed to clarify the mechanism of its intestinal absorption. ALG uptake into Caco-2 cells was time-, temperature-, and concentration-dependent, but was not saturated at concentrations up to 10 mmol/L. The uptake was significantly inhibited by the organic anion transporting polypeptide (OATP) substrate fexofenadine and by the OATP inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), but was not inhibited by organic cation transporter (OCT)/organic cation/carnitine transporter (OCTN) or peptide transporter 1 (PEPT1) substrates. Grapefruit, orange, and apple juices and their constituents, which are known to strongly inhibit intestinal OATPs, significantly inhibited ALG uptake into Caco-2 cells. The pH dependence was bell-shaped, indicating the involvement of a pH-sensitive transporter. However, ALG uptake by HEK293 cells overexpressing OATP2B1, a key intestinal OATP transporter of amphiphilic drugs, was not different from that of mock cells. In a rat in vivo study, apple juice reduced systemic exposure to orally administered ALG without changing the terminal half-life. These observations suggest that intestinal absorption of ALG is carrier-mediated, and involves a fruit-juice-sensitive transporter other than OATP2B1.