Fruit juice inhibition of uptake transport: a new type of food-drug interaction
TL;DR: A new type of interaction in which fruit juices diminish oral drug bioavailability through inhibition of uptake transport is the focus of this review and knowledge of both affected uptake transporter and drug hydrophilicity assisted prediction of the clinical interaction with grapefruit or orange juice.
Abstract: A new type of interaction in which fruit juices diminish oral drug bioavailability through inhibition of uptake transport is the focus of this review. The discovery was based on an opposite to anticipated finding when assessing the possibility of grapefruit juice increasing oral fexofenadine bioavailability in humans through inhibition of intestinal MDR1-mediated efflux transport. In follow-up investigations, grapefruit or orange juice at low concentrations potentially and selectively inhibited in vitro OATP1A2-mediated uptake compared with MDR1-caused efflux substrate transport. These juices at high volume dramatically depressed oral fexofenadine bioavailability. Grapefruit was the representative juice to characterize the interaction subsequently. A volume–effect relationship study using a normal juice amount halved average fexofenadine absorption. Individual variability and reproducibility data indicated the clinical interaction involved direct inhibition of intestinal OATP1A2. Naringin was a major causal component suggesting that other flavonoids in fruits and vegetables might also produce the effect. Duration of juice clinical inhibition of fexofenadine absorption lasted more than 2 h but less than 4 h indicating the interaction was avoidable with appropriate interval of time between juice and drug consumption. Grapefruit juice lowered the oral bioavailability of several medications transported by OATP1A2 (acebutolol, celiprolol, fexofenadine, talinolol, L-thyroxine) while orange juice did the same for others (atenolol, celiprolol, ciprofloxacin, fexofenadine). Juice clinical inhibition of OATP2B1 was unresolved while that of OATP1B1 seemed unlikely. The interaction between grapefruit juice and etoposide also seemed relevant. Knowledge of both affected uptake transporter and drug hydrophilicity assisted prediction of the clinical interaction with grapefruit or orange juice.
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TL;DR: The biologic activities of naringin and its aglycone naringenin are explored, particularly on lipid metabolism in obesity, oxidative stress, and inflammation in context of metabolic syndrome.
498 citations
TL;DR: A review of clinically observed drug-drug interactions attributable to inhibition or induction of intestinal export transporters, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and the impact of nutrition on transport processes as well as genotype-dependent, transporter-mediated drug- drug interactions will be discussed.
Abstract: Uptake and efflux transporters determine plasma and tissue concentrations of a broad variety of drugs. They are localized in organs such as small intestine, liver, and kidney, which are critical for drug absorption and elimination. Moreover, they can be found in important blood-tissue barriers such as the blood-brain barrier. Inhibition or induction of drug transporters by coadministered drugs can alter pharmacokinetics and pharmacodynamics of the victim drugs. This review will summarize in particular clinically observed drug-drug interactions attributable to inhibition or induction of intestinal export transporters [P-glycoprotein (P-gp), breast cancer resistance protein (BCRP)], to inhibition of hepatic uptake transporters [organic anion transporting polypeptides (OATPs)], or to inhibition of transporter-mediated [organic anion transporters (OATs), organic cation transporter 2 (OCT2), multidrug and toxin extrusion proteins (MATEs), P-gp] renal secretion of xenobiotics. Available data on the impact of nutrition on transport processes as well as genotype-dependent, transporter-mediated drug-drug interactions will be discussed. We will also present and discuss data on the variable extent to which information on the impact of transporters on drug disposition is included in summaries of product characteristics of selected countries (SPCs). Further work is required regarding a better understanding of the role of the drug metabolism-drug transport interplay for drug-drug interactions and on the extrapolation of in vitro findings to the in vivo (human) situation.
496 citations
Cites background from "Fruit juice inhibition of uptake tr..."
...More recently, inhibition of intestinal uptake and efflux transporters has intensively been studied as a potential mechanism of drug-food interactions (for review, see Greenblatt, 2009; Bailey, 2010; Won et al., 2010)....
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...2 and 3 (Thiebaut et al., 1987)] mediating the export of xenobiotics into bile and urine, respectively....
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...Today, more than 30 clinically relevant drugs have been identified as inhibitors or substrates of MATE1 and MATE2-K, including cimetidine, acyclovir, metformin, the antiarrhythmic drug procainamide, and the antineoplastic agent topotecan....
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...Apple juice coadministration also resulted in reduced plasma concentrations of some drugs [e.g., atenolol, celiprolol, ciprofloxacin, fexofenadine (Bailey, 2010)]....
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TL;DR: The time is right for a systematic attack on SLC structure, specificity, and function, taking into account kinship and expression, as well as the dependencies that arise from the common metabolic space.
420 citations
Cites background from "Fruit juice inhibition of uptake tr..."
...For example, naringin from citrus fruits inhibits the enterohepatic transporter SLCO1A2 and thus can reduce the bioavailability of drugs that rely on this transporter, such as fexofenadine (Bailey, 2010)....
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TL;DR: Important advances include improved nasal and ophthalmic H(1)-antihistamines with rapid onset of action (in minutes) for allergic rhinitis and allergic conjunctivitis treatment, respectively, and effective and safe use of high (up to 4-fold) doses of oral second-generation H( 1)-anthistamines for chronic urticaria treatment.
Abstract: In this review we celebrate a century of progress since the initial description of the physiologic and pathologic roles of histamine and 70 years of progress since the introduction of H(1)-antihistamines for clinical use. We discuss histamine and clinically relevant information about the molecular mechanisms of action of H(1)-antihistamines as inverse agonists (not antagonists or blockers) with immunoregulatory effects. Unlike first (old)-generation H(1)-antihistamines introduced from 1942 to the mid-1980s, most of the second (new)-generation H(1)-antihistamines introduced subsequently have been investigated extensively with regard to clinical pharmacology, efficacy, and safety; moreover, they are relatively free from adverse effects and not causally linked with fatalities after overdose. Important advances include improved nasal and ophthalmic H(1)-antihistamines with rapid onset of action (in minutes) for allergic rhinitis and allergic conjunctivitis treatment, respectively, and effective and safe use of high (up to 4-fold) doses of oral second-generation H(1)-antihistamines for chronic urticaria treatment. New H(1)-antihistamines introduced for clinical use include oral formulations (bilastine and rupatadine), and ophthalmic formulations (alcaftadine and bepotastine). Clinical studies of H(3)-antihistamines with enhanced decongestant effects have been conducted in patients with allergic rhinitis. Additional novel compounds being studied include H(4)-antihistamines with anti-inflammatory effects in allergic rhinitis, atopic dermatitis, and other diseases. Antihistamines have a storied past and a promising future.
403 citations
Cites background from "Fruit juice inhibition of uptake tr..."
...Their drug-drug, drug-food, and drug–herbal product interactions, if any, are well characterized and seldom clinically relevant (Table III and see Table E1).1,18,34-37 The pharmacodynamics of most orally administered secondgeneration H1-antihistamines have been assessed by measuring suppressionof the histamine-inducedwheals andflares (erythema), which correlates better with H1-receptor occupancy by free unbound drug than with H1-antihistamine concentrations in plasma or even in tissue....
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...Their drug-drug, drug-food, and drug–herbal product interactions, if any, are well characterized and seldom clinically relevant (Table III and see Table E1).(1,18,34-37) The pharmacodynamics of most orally administered secondgeneration H1-antihistamines have been assessed by measuring suppressionof the histamine-inducedwheals andflares (erythema), which correlates better with H1-receptor occupancy by free unbound drug than with H1-antihistamine concentrations in plasma or even in tissue....
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...After discontinuation of regular daily dosing, residual effects, such as suppression of allergy skin test responses, last from 1 to 5 days (Table III and see Table E1).1,34,37-41 J ALLERGY CLIN IMMUNOL DECEMBER 2011 1142 SIMONS AND SIMONS In patients with allergic rhinitis and allergic conjunctivitis, suppression of the response to nasal or conjunctival allergen challenge tests by H1-antihistamines regardless of route of administration provides clinically relevant information about their onset, extent, and duration of action....
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...Information about pharmacokinetics and pharmacodynamics in healthy adults, elderly people, children, infants, and other vulnerable patients is therefore not available for most of them, and few drug interaction studies have been performed with them (see Table E1 in this article’s Online Repository at www.jacionline.org).1,18 Second (new)–generation H1-antihistamines Formost second-generationH1-antihistamines, pharmacokinetics have been extensively investigated in healthy adults, patients with impaired hepatic or renal function, and elderly people, children, and infants....
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...*Please see Table E1 for additional information....
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TL;DR: This introductory overview of food adulteration and contamination practices is hoped that it acts as a springboard for researchers in science, technology, engineering, and industry, in this era of systems-level thinking and interdisciplinary approaches to new and contemporary problems.
Abstract: Major food adulteration and contamination events seem to occur with some regularity, such as the widely publicised adulteration of milk products with melamine and the recent microbial contamination of vegetables across Europe for example. With globalisation and rapid distribution systems, these can have international impacts with far-reaching and sometimes lethal consequences. These events, though potentially global in the modern era, are in fact far from contemporary, and deliberate adulteration of food products is probably as old as the food processing and production systems themselves. This review first introduces some background into these practices, both historically and contemporary, before introducing a range of the technologies currently available for the detection of food adulteration and contamination. These methods include the vibrational spectroscopies: near-infrared, mid-infrared, Raman; NMR spectroscopy, as well as a range of mass spectrometry (MS) techniques, amongst others. This subject area is particularly relevant at this time, as it not only concerns the continuous engagement with food adulterers, but also more recent issues such as food security, bioterrorism and climate change. It is hoped that this introductory overview acts as a springboard for researchers in science, technology, engineering, and industry, in this era of systems-level thinking and interdisciplinary approaches to new and contemporary problems.
324 citations
References
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TL;DR: This article focuses on the cytochrome P-450 enzymes, a superfamily of microsomal drug-metabolizing enzymes that play an important role in oxidative drug metabolism.
Abstract: Differences in drug responsiveness are common, often leading to challenges in optimizing the dosage regimen for a particular patient. Recent advances provide a rational framework for understanding many interpatient differences in drug disposition and their clinical consequences. This article focuses on the cytochrome P-450 enzymes, a superfamily of microsomal drug-metabolizing enzymes that play an important role in oxidative drug metabolism.
1,004 citations
TL;DR: The clinical importance of any drug interaction depends on factors that are drug-, patient- and administration-related and is likely to be dependent on interindividual differences in CYP3A4 tissue content, pre-existing medical conditions and, possibly, age.
Abstract: Drug interactions occur when the efficacy or toxicity of a medication is changed by administration of another substance. Pharmacokinetic interactions often occur as a result of a change in drug metabolism. Cytochrome P450 (CYP) 3A4 oxidises a broad spectrum of drugs by a number of metabolic processes. The location of CYP3A4 in the small bowel and liver permits an effect on both presystemic and systemic drug disposition. Some interactions with CYP3A4 inhibitors may also involve inhibition of P-glycoprotein.
868 citations
TL;DR: The effects of cyclosporine and gemfibrozil explain the increased plasma statin concentrations and, together with pharmacodynamic factors, the increased risk of myotoxicity when coadministered with statins.
Abstract: Lipid-lowering drugs, especially 3-hydroxy-3-methylglutaryl-coenzyme A inhibitors (statins), are widely used in the treatment and prevention of atherosclerotic disease. The benefits of statins are well documented. However, lipid-lowering drugs may cause myopathy, even rhabdomyolysis, the risk of which is increased by certain interactions. Simvastatin, lovastatin, and atorvastatin are metabolized by cytochrome P450 (CYP) 3A4 (simvastatin acid is also metabolized by CYP2C8); their plasma concentrations and risk of myotoxicity are greatly increased by strong inhibitors of CYP3A4 (eg, itraconazole and ritonavir). Weak or moderately potent CYP3A4 inhibitors (eg, verapamil and diltiazem) can be used cautiously with small doses of CYP3A4-dependent statins. Cerivastatin is metabolized by CYP2C8 and CYP3A4, and fluvastatin is metabolized by CYP2C9. The exposure to fluvastatin is increased by less than 2-fold by inhibitors of CYP2C9. Pravastatin, rosuvastatin, and pitavastatin are excreted mainly unchanged, and their plasma concentrations are not significantly increased by pure CYP3A4 inhibitors. Cyclosporine (INN, ciclosporin) inhibits CYP3A4, P-glycoprotein (multidrug resistance protein 1), organic anion transporting polypeptide 1B1 (OATP1B1), and some other hepatic uptake transporters. Gemfibrozil and its glucuronide inhibit CYP2C8 and OATP1B1. These effects of cyclosporine and gemfibrozil explain the increased plasma statin concentrations and, together with pharmacodynamic factors, the increased risk of myotoxicity when coadministered with statins. Inhibitors of OATP1B1 may decrease the benefit/risk ratio of statins by interfering with their entry into hepatocytes, the site of action. Lipid-lowering drugs can be involved also in other interactions, including those between enzyme inducers and CYP3A4 substrate statins, as well as those between gemfibrozil and CYP2C8 substrate antidiabetics. Knowledge of the pharmacokinetic and pharmacodynamic properties of lipid-lowering drugs and their interaction mechanisms helps to avoid adverse interactions, without compromising therapeutic benefits.
756 citations
TL;DR: In vitro findings support the flavonoid, naringin, or the furanocoumarin, 6',7'-dihydroxybergamottin, as being active ingredients, but a recent investigation indicated that neither of these substances made a major contribution to grapefruit juice-drug interactions in humans.
Abstract: The novel finding that grapefruit juice can markedly augment oral drug bioavailability was based on an unexpected observation from an interaction study between the dihydropyridine calcium channel antagonist, felodipine, and ethanol in which grapefruit juice was used to mask the taste of the ethanol. Subsequent investigations showed that grapefruit juice acted by reducing presystemic felodipine metabolism through selective post-translational down regulation of cytochrome P450 3A4 (CYP3A4) expression in the intestinal wall. Since the duration of effect of grapefruit juice can last 24 h, repeated juice consumption can result in a cumulative increase in felodipine AUC and Cmax. The high variability of the magnitude of effect among individuals appeared dependent upon inherent differences in enteric CYP3A4 protein expression such that individuals with highest baseline CYP3A4 had the highest proportional increase. At least 20 other drugs have been assessed for an interaction with grapefruit juice. Medications with innately low oral bioavailability because of substantial presystemic metabolism mediated by CYP3A4 appear affected by grapefruit juice. Clinically relevant interactions seem likely for most dihydropyridines, terfenadine, saquinavir, cyclosporin, midazolam, triazolam and verapamil and may also occur with lovastatin, cisapride and astemizole. The importance of the interaction appears to be influenced by individual patient susceptibility, type and amount of grapefruit juice and administration-related factors. Although in vitro findings support the flavonoid, naringin, or the furanocoumarin, 6',7'-dihydroxybergamottin, as being active ingredients, a recent investigation indicated that neither of these substances made a major contribution to grapefruit juice-drug interactions in humans.
746 citations
TL;DR: A mechanism for the effect of grapefruit juice on oral felodipine kinetics is its selective downregulation of CYP3A4 in the small intestine.
Abstract: The increase in oral availability of felodipine and other commonly used medications when taken with grapefruit juice has been assumed to be due to inhibition of CYP3A4, a cytochrome P450 that is present in liver and intestine. To evaluate the effect of repeated grapefruit juice ingestion on CYP3A4 expression, 10 healthy men were given 8 oz of grapefruit juice three times a day for 6 d. Before and after receiving grapefruit juice, small bowel and colon mucosal biopsies were obtained endoscopically, oral felodipine kinetics were determined, and liver CYP3A4 activity was measured with the [14C N-methyl] erythromycin breath test in each subject. Grapefruit juice did not alter liver CYP3A4 activity, colon levels of CYP3A5, or small bowel concentrations of P-glycoprotein, villin, CYP1A1, and CYP2D6. In contrast, the concentration of CYP3A4 in small bowel epithelia (enterocytes) fell 62% (P = 0.0006) with no corresponding change in CYP3A4 mRNA levels. In addition, enterocyte concentrations of CYP3A4 measured before grapefruit juice consumption correlated with the increase in Cmax when felodipine was taken with either the 1st or the 16th glass of grapefruit juice relative to water (r = 0. 67, P = 0.043, and r = 0.71, P = 0.022, respectively). We conclude that a mechanism for the effect of grapefruit juice on oral felodipine kinetics is its selective downregulation of CYP3A4 in the small intestine.
628 citations