Grapefruit–drug interactions

Last updated

Grapefruit Juice and Medicine May Not Mix (6774935740) - en.svg

Some fruit juices and fruits can interact with numerous drugs, in many cases causing adverse effects. [1] The effect is most studied with grapefruit and grapefruit juice, [1] but similar effects have been observed with certain other citrus fruits. [1] [2] [3] [4]

Contents

One whole grapefruit, or a small glass (200 mL, 6.8 US fl oz) of grapefruit juice, can cause drug overdose toxicity. [1] Fruit consumed three days before the medicine can still have an effect. [5] The relative risks of different types of citrus fruit have not been systematically studied. [1] Affected drugs typically have an auxiliary label saying "Do not take with grapefruit" on the container, and the interaction is elaborated upon in the package insert. [6] People are also advised to ask their physician or pharmacist about drug interactions. [6] However, some experts believe that for the majority of patients, complete avoidance of grapefruit is unwarranted. [7]

Although a prospective cohort study of middle-aged women indicated that some flavonoid-rich foods are associated with a reduction in all-cause mortality, frequent grapefruit consumption was associated with a small increase in all-cause mortality, possibly because of the clinically significant drug interactions of the non-flavonoid components. [8]

History

The effect of grapefruit juice with regard to drug absorption was originally discovered in 1989 by a group led by pharmacologist David Bailey. Their first published clinical report on grapefruit drug interactions was in 1991. [9] The effect was first discovered accidentally in 1989, when a test of drug interactions with alcohol used grapefruit juice to hide the taste of the ethanol. [9] [10] A 2005 medical review advised patients to avoid all citrus juices until further research clarifies the risks. [11] It was reported in 2008 that similar effects had been observed with apple juice. [2] [12] [13]

Polyphenols

Citrus fruits contain various polyphenols, which may include furanocoumarins and naringin, such as bergamottin, dihydroxybergamottin, and bergapten. [14] Grapefruit, Seville oranges, [15] and bergamot [16] contain naringin. Furanocoumarins may have a stronger effect than naringin. [15] [17]

Mechanism

The effects are caused by furanocoumarins (and, to a lesser extent, flavonoids) which are compounds produced by many plants including but not limited to grapefruit. [18] These chemicals inhibit key drug metabolizing enzymes, such as cytochrome P450 3A4 (CYP3A4). CYP3A4 is a metabolizing enzyme for almost 50% of drugs, and is found in the liver and small intestinal epithelial cells. [19] Organic derivatives of furanocoumarin interfere with liver and intestinal enzyme CYP3A4 and may be responsible for the effects of grapefruit on the enzyme. [20] Cytochrome isoforms affected by grapefruit components also include CYP1A2, CYP2C9, and CYP2D6, [21] [22] [23] [24] [25] but CYP3A4 is the major CYP enzyme in the intestine. [26]

Inhibition of enzymes can have two different effects:

  1. grapefruit juice-mediated inhibition of enzymes that metabolize the drug to an inactive metabolite leads to too high doses of the drug in the body [27]
  2. grapefruit juice-mediated inhibition of membrane transport proteins from the intestine to the blood, or inhibition of enzymes that activates a prodrug to an active metabolite leads to insufficient doses of the drug in the body resulting in loss of theurapeutic effect [27]

Grapefruit or grapefruit juice can also reduce the absorption of many drugs by inhibiting transport across cell membranes, by the transporters P-glycoprotein (a member of the superfamily of ATP-binding cassette (ABC) transporters) and members of the organo anion transporter family. [26] [7] These transporters appear to have a minimal effect on systemic exposure of the drugs they affect, however. [7] Many drugs are affected by consumption of citrus juice. When the metabolizing enzyme is inhibited, less of the drug will be metabolized by it in the epithelial cells. [19] This interaction is particularly dangerous when the drug in question has a low therapeutic index, so that a small increase in blood concentration can be the difference between therapeutic effect and toxicity. Citrus juice inhibits the enzyme only within the intestines if consumed in small amounts. When larger amounts are consumed they may also inhibit the enzyme in the liver. The hepatic enzyme inhibition may cause an additional increase in potency and a prolonged metabolic half-life (prolonged metabolic half-life for all ways of drug administration). [28]

Duration and timing

Metabolism interactions

Grapefruit–drug interactions that affect the pre-systemic metabolism (i.e., the metabolism that occurs before the drug enters the blood) of drugs have a different duration of action than interactions that work by other mechanisms, such as on absorption, discussed below. [19]

The interaction is greatest when the juice is ingested with the drug or up to 4 hours before the drug. [1] [5] [29]

The location of the inhibition occurs in the lining of the intestines, not within the liver. [30] The effects last because grapefruit-mediated inhibition of drug metabolizing enzymes, like CYP3A4, is irreversible; [30] that is, once the grapefruit has "broken" the enzyme, the intestinal cells must produce more of the enzyme to restore their capacity to metabolize drugs that the enzyme is used to metabolize. [19] It takes around 24 hours to regain 50% of the cell's baseline enzyme activity and it can take 72 hours for the enzyme activity to completely return to baseline. For this reason, simply separating citrus consumption and medications taken daily does not avoid the drug interaction. [5]

Absorption interactions

For medications that interact due to inhibition of OATP (organic anion-transporting polypeptides), a relative short period of time is needed to avoid this interaction, and a 4-hour interval between grapefruit consumption and the medication should suffice. [19] [31] For drugs recently sold on the market, drugs have information pages (monographs) that provide information on any potential interaction between a medication and grapefruit juice. [19] Because there is a growing number of medications that are known to interact with citrus, [1] patients should consult a pharmacist or physician before consuming citrus while taking their medications.

Affected fruit

Grapefruit is not the only citrus fruit that can interact with medications. [1] [2] [3] [4] One medical review advised patients to avoid all citrus. [11]

There are three ways to test if a fruit interacts with drugs:

  1. Test a drug–fruit combination in humans [11]
  2. Test a fruit chemically for the presence of the interacting polyphenol compounds
  3. Test a fruit genetically for the genes needed to make the interacting polyphenol compounds [32]

The first approach involves risk to trial volunteers. The first and second approaches have another problem: the same fruit cultivar could be tested twice with different results. Depending on growing and processing conditions, concentrations of the interacting polyphenol compounds can vary dramatically. The third approach is hampered by a paucity of knowledge of the genes in question. [32]

Citrus genetics and interactions

Citrus fruits clustered by genetic similarity. Most commercial varieties of citrus are hybrids of the three species at the corners of the ternary diagram, and genetically distinct hybrids often bear the same common name. Furanocoumarin production has been inherited by some hybrid cultivars; others have not inherited the furanocoumarin-producing genes. Citrus tern cb simplified 1.svg
Citrus fruits clustered by genetic similarity. Most commercial varieties of citrus are hybrids of the three species at the corners of the ternary diagram, and genetically distinct hybrids often bear the same common name. Furanocoumarin production has been inherited by some hybrid cultivars; others have not inherited the furanocoumarin-producing genes.

A descendant of citrus cultivars that cannot produce the problematic polyphenol compounds would presumably also lack the genes to produce them. Many citrus cultivars are hybrids of a small number of ancestral species, which have now been fully genetically sequenced. [33] [34]

Many traditional citrus groups, such as true sweet oranges and lemons, seem to be bud sports, mutant descendants of a single hybrid ancestor. [35] In theory, cultivars in a bud sport group would be either all safe or all problematic. Nonetheless, new citrus varieties arriving on the market are increasingly likely to be sexually created hybrids, not asexually created sports.

The ancestry of a hybrid cultivar may not be known. Even if it is known, it is not possible to be certain that a cultivar will not interact with drugs on the basis of taxonomy, as it is not known which ancestors lack the capacity to make the problematic polyphenol compounds. Nonetheless, many of the citrus cultivars known to be problematic seem to be closely related.

Ancestral species

Pomelo (the Asian fruit that was crossed with an orange to produce grapefruit) contains high amounts of furanocoumarin derivatives. Grapefruit relatives and other varieties of pomelo have variable amounts of furanocoumarin. [11] [2] [36] [37]

The Dancy cultivar has a small amount of pomelo ancestry, [34] but is genetically close to a non-hybrid true mandarin (unlike most commercial mandarins, which may have much more extensive hybridization). Eight Dancy fruits, all picked at one time from one tree, have been blended and tested for furanocoumarins; none were detectable. [36]

No citron or papeda seems to have been tested.[ citation needed ]

Hybrid cultivars

Both sweet oranges and bitter oranges are mandarin-pomelo hybrids. [34] [35] Bitter oranges (such as the Seville oranges often used in marmalade) can interfere with drugs [38] including etoposide, a chemotherapy drug, some beta blocker drugs used to treat high blood pressure, and cyclosporine, taken by transplant patients to prevent rejection of their new organs. [12] Evidence on sweet oranges is more mixed. [11]

Tests on some tangelos (hybrids of mandarins/tangerines and pomelo or grapefruit) have not shown significant amounts of furanocoumarin; these studies were also conducted on eight fruit all picked at one time from one tree. [36]

Common lemons are the product of orange/citron hybridization, and hence have pomelo ancestry, and although Key limes are papeda/citron hybrids, the more commercially prevalent Persian limes and similar varieties are crosses of the Key lime with lemons, and hence likewise have pomelo ancestry. [33] [34] These limes can also inhibit drug metabolism. [38] Other less-common citrus species also referred to as lemons or limes are genetically distinct from the more common varieties, with different proportions of pomelo ancestry. [33]

Inaccurate labeling

Marketing classifications often do not correspond to taxonomic ones. The "Ambersweet" cultivar is marketed and sold as an orange, but does not descend from the same common ancestor as sweet oranges; it has grapefruit, orange, and mandarin ancestry. Fruits are often sold as mandarin, tangerine, or satsuma (which may be synonyms [39] ). Fruit sold under these names include many that are, like Sunbursts and Murcotts, hybrids with grapefruit ancestry. [36] [40] [41]

Other fruit and vegetables

The discovery that flavonoids are responsible for some interactions make it plausible that other fruit and vegetables are affected. [31]

Apple juice

Apple juice, especially commercially produced products, interferes with the action of OATPs. [42] This interference can decrease the absorption of a variety of commonly used medications, including beta blockers like atenolol, antibiotics like ciprofloxacin, and antihistamines like montelukast. [42] [43]

Pomegranate juice

Pomegranate juice inhibits the action of the drug metabolizing enzymes CYP2C9 and CYP3A4. [44] As of 2014, however, the currently available literature does not appear to indicate a clinically relevant impact of pomegranate juice on drugs that are metabolized by CYP2C9 and CYP3A4. [44]

Affected drugs

Researchers have identified over 85 drugs with which grapefruit reacts adversely. [45] [1] According to a review done by the Canadian Medical Association, [1] there is an increase in the number of potential drugs that can interact with grapefruit juice, and of the number of fruit types that can interact with those drugs. From 2008 to 2012, the number of drugs known to potentially interact with grapefruit, with risk of harmful or even dangerous effects (gastrointestinal bleeding, nephrotoxicity), increased from 17 to 43. [1]

Traits

The interaction between citrus and medication depends on the individual drug, and not the class of the drug. Drugs that interact usually share three common features: they are taken orally, normally only a small amount enters systemic blood circulation, and they are metabolized by CYP3A4. [1] The effects on the CYP3A4 in the liver could, in principle, cause interactions with non-oral drugs (e.g. parenteral, inhaled substances, transdermal),[ citation needed ] and non-CYP3A4-mediated effects also exist. [31]

Cytochrome isoforms affected by grapefruit components include CYP3A4, CYP1A2, CYP2C9, and CYP2D6. [21] Drugs that are metabolized by these enzymes may have interactions with components of grapefruit.

An easy way to tell if a medication may be affected by grapefruit juice is by researching whether another known CYP3A4 inhibitor drug is already contraindicated with the active drug of the medication in question. Examples of such known CYP3A4 inhibitors include cisapride (Propulsid), [46] erythromycin, itraconazole (Sporanox), ketoconazole (Nizoral), and mibefradil (Posicor). [47]

Incomplete list of affected drugs

By enzyme

Drugs that interact with grapefruit compounds at CYP3A4 include

Drugs that interact with grapefruit compounds at CYP1A2 include

Drugs that interact with grapefruit compounds at CYP2D6 include

Research has been done on the interaction between amphetamines and CYP2D6 enzyme, and researchers concluded that some parts of substrate molecules contribute to the binding of the enzyme. [59]

Other interactions

Additional drugs affected by grapefruit juice include, but are not limited to:

  • Some statins, including atorvastatin (Lipitor), [60] lovastatin (Mevacor), and simvastatin (Zocor, Simlup, Simcor, Simvacor) [61]
  • Anti-arrhythmics including amiodarone (Cordarone), [62] dronedarone (Multaq), quinidine (Quinidex, Cardioquin, Quinora), disopyramide (Norpace), propafenone (Rythmol) and carvedilol (Coreg) [61]
  • Amlodipine: Grapefruit increases the available amount of the drug in the blood stream, leading to an unpredictable increase in antihypertensive effects.
  • Anti-migraine drugs ergotamine (Cafergot, Ergomar), amitriptyline (Elavil, Endep, Vanatrip) and nimodipine (Nimotop) [61]
  • Erectile dysfunction drugs sildenafil (Viagra), tadalafil (Cialis) and vardenafil (Levitra) [61] [63]
  • Acetaminophen (also known as paracetamol, brand name Tylenol) concentrations were found to be increased in murine blood by white and pink grapefruit juice, with the white juice acting faster. [64] "The bioavailability of paracetamol was significantly reduced following multiple GFJ administration" in mice and rats. This suggests that repeated intake of grapefruit juice reduces the efficacy and bioavailability of acetaminophen/paracetamol in comparison with a single dose of grapefruit juice, which conversely increases the efficacy and bioavailability of acetaminophen/paracetamol. [65] [66]
  • Anthelmintics: Used for treating certain parasitic infections; includes praziquantel
  • Buprenorphine: Metabolized into norbuprenorphine by CYP3A4 [67]
  • Buspirone (Buspar): Grapefruit juice increased peak and AUC plasma concentrations of buspirone 4.3- and 9.2-fold, respectively, in a randomized, 2-phase, ten-subject crossover study. [68]
  • Codeine is a prodrug that produces its analgesic properties following metabolism to morphine entirely by CYP2D6. [69]
  • Ciclosporin (cyclosporine, Neoral): Blood levels of ciclosporin are increased if taken with grapefruit juice, orange juice, or apple juice. [12] A plausible mechanism involves the combined inhibition of enteric CYP3A4 and MDR1, which potentially leads to serious adverse events (e.g., nephrotoxicity). Blood levels of tacrolimus (Prograf) can also be equally affected for the same reason as ciclosporin, as both drugs are calcineurin inhibitors. [70]
  • Dihydropyridines including felodipine (Plendil), nicardipine (Cardene), nifedipine, nisoldipine (Sular) and nitrendipine (Bayotensin) [61]
  • Erlotinib (Tarceva) [71]
  • Exemestane, aromasin, and by extension all estrogen-like compounds and aromatase inhibitors that mimic estrogen in function will be increased in effect, causing increased estrogen retention and increased drug retention. [72]
  • Etoposide interferes with grapefruit, orange, and apple juices. [12]
  • Fexofenadine (Allegra) concentrations are decreased rather than increased as is the case with most grapefruit–drug interactions. [73] [74]
  • Fluvoxamine (Luvox, Faverin, Fevarin and Dumyrox) [75]
  • Imatinib (Gleevec): Although no formal studies with imatinib and grapefruit juice have been conducted, the fact that grapefruit juice is a known inhibitor of the CYP 3A4 suggests that co-administration may lead to increased imatinib plasma concentrations. Likewise, although no formal studies were conducted, co-administration of imatinib with another specific type of citrus juice called Seville orange juice (SOJ) may lead to increased imatinib plasma concentrations via inhibition of the CYP3A isoenzymes. Seville orange juice is not usually consumed as a juice because of its sour taste, but it is found in marmalade and other jams. Seville orange juice has been reported to be a possible inhibitor of CYP3A enzymes without affecting MDR1 when taken concomitantly with ciclosporin. [76]
  • Ketamine: After drinking 200 mL of grapefruit juice daily for five days, the overall absorption of orally ingested ketamine was increased three-fold compared to the control group in a clinical trial. The peak blood ketamine concentration was increased over two-fold. [77]
  • Levothyroxine (Eltroxin, Levoxyl, Synthroid): "Grapefruit juice may slightly delay the absorption of levothyroxine, but it seems to have only a minor effect on its bioavailability."[ clarification needed ] [78]
  • Losartan (Cozaar) [61]
  • Methadone: Inhibits the metabolism of methadone and raises serum levels. [79]
  • Omeprazole (Losec, Prilosec) [80]
  • Oxycodone: Grapefruit juice enhances the exposure to oral oxycodone. In a randomized, controlled trial 12 healthy volunteers ingested 200 mL of either grapefruit juice or water three times daily for five days. On the fourth day 10 mg of oxycodone hydrochloride were administered orally. Analgesic and behavioral effects were reported for 12 hours and plasma samples were analyzed for oxycodone metabolites for 48 hours. Grapefruit juice increased the mean area under the oxycodone concentration-time curve (AUC(0-∞)) by 1.7 fold, the peak plasma concentration by 1.5-fold and the half-life of oxycodone by 1.2-fold as compared to water. The metabolite-to-parent ratios of noroxycodone and noroxymorphone decreased by 44% and 45% respectively. Oxymorphone AUC(0-∞) increased by 1.6-fold but the metabolite-to-parent ratio remained unchanged. [81]
  • Quetiapine (Seroquel) [82]
  • Repaglinide (Prandin) [61]
  • Sirolimus (Rapamycin, Rapamune) [83]
  • Tamoxifen (Nolvadex): Tamoxifen is metabolized by CYP2D6 into its active metabolite 4-hydroxytamoxifen. Grapefruit juice may potentially reduce the effectiveness of tamoxifen. [84]
  • Trazodone (Desyrel): Little or no interaction with grapefruit juice. [85]
  • Verapamil (Calan SR, Covera HS, Isoptin SR, Verelan): atrioventricular conduction disorders. [61]
  • Warfarin (coumadin) [86]
  • Zolpidem (Ambien): Little or no interaction with grapefruit juice [85]
Drugs affected by grapefruit juice
Drug classMajor InteractionsMinor interactions
Antiarrhythmic agents amiodarone (Cordarone)
dronedarone (Multaq)
dofetilide (Tikosyn)
Antihistamines terfenadine (Seldane) (off the market)
diphenhydramine (Benadryl) (partially)
astemizole (Hismanal) (off the market)
Calcium channel antagonists felodipine (Plendil)
nicardipine (Cardene)
nifedipine (Procardia)
nimodipine (Nimotop)
nisoldipine (Sular)
isradipine (DynaCirc)
Statins (HMG-CoA reductase inhibitors) simvastatin (Zocor)
lovastatin (Mevacor)		 atorvastatin (Lipitor)
cerivastatin (Baycol) (off the market)
Cough Suppressant/NMDA Antagonist dextromethorphan
Erectile dysfunction drugs sildenafil (Viagra)
tadalafil (Cialis)
vardenafil (Levitra)
HIV protease inhibitors saquinavir (Invirase)
ritonavir (Norvir)
nelfinavir (Viracept)
amprenavir (Agenerase)
Hormones ethinylestradiol (Ortho-Cept, many others)
methylprednisolone (Medrol)
Immunosuppressants ciclosporin (Sandimmune Neoral)
tacrolimus (Prograf)
sirolimus (Rapamune)
mercaptopurine
Sedatives, hypnotics, and anxiolytics buspirone (Buspar) triazolam (Halcion)
midazolam (Versed)
diazepam (Valium)
zaleplon (Sonata)
alprazolam (Xanax)

clonazepam (Klonopin)

ketamine

Other psychotropics carbamazepine (Tegretol)
trazodone (Desyrel)
quetiapine (Seroquel)
fluvoxamine (Luvox)
nefazodone (Serzone)
Other miscellaneous drugs cisapride (Prepulsid, Propulsid) [46]
ivabradine (Corlanor) [87]

Related Research Articles

<span class="mw-page-title-main">Grapefruit</span> Citrus fruit

The grapefruit is a subtropical citrus tree known for its relatively large, sour to semi-sweet, somewhat bitter fruit. The flesh of the fruit is segmented and varies in color from pale yellow to dark red.

<span class="mw-page-title-main">Amitriptyline</span> Tricyclic antidepressant

Amitriptyline, sold under the brand name Elavil among others, is a tricyclic antidepressant primarily used to treat major depressive disorder, and a variety of pain syndromes such as neuropathic pain, fibromyalgia, migraine and tension headaches. Due to the frequency and prominence of side effects, amitriptyline is generally considered a second-line therapy for these indications.

<span class="mw-page-title-main">Cimetidine</span> Medication

Cimetidine, sold under the brand name Tagamet among others, is a histamine H2 receptor antagonist that inhibits stomach acid production. It is mainly used in the treatment of heartburn and peptic ulcers.

<span class="mw-page-title-main">CYP3A4</span> Enzyme that metabolizes substances by oxidation

Cytochrome P450 3A4 is an important enzyme in the body, mainly found in the liver and in the intestine, which in humans is encoded by CYP3A4 gene. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from the body. It is highly homologous to CYP3A5, another important CYP3A enzyme.

<span class="mw-page-title-main">CYP2D6</span> Human liver enzyme

Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the CYP2D6 gene. CYP2D6 is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra.

<span class="mw-page-title-main">Drug interaction</span> Change in the action or side effects of a drug caused

In pharmaceutical sciences, drug interactions occur when a drug's mechanism of action is affected by the concomitant administration of substances such as foods, beverages, or other drugs. A popular example of drug–food interaction is the effect of grapefruit on the metabolism of drugs.

<span class="mw-page-title-main">Dextromethorphan</span> Cough suppressant, antidepressant, and dissociative drug

Dextromethorphan, sold under the brand name Robitussin among others, is a cough suppressant used in many cough and cold medicines. In 2022, the US Food and Drug Administration (FDA) approved the combination dextromethorphan/bupropion to serve as a rapid-acting antidepressant in people with major depressive disorder.

<span class="mw-page-title-main">Cilostazol</span> Chemical compound

Cilostazol, sold under the brand name Pletal among others, is a medication used to help the symptoms of intermittent claudication in peripheral vascular disease. If no improvement is seen after 3 months, stopping the medication is reasonable. It may also be used to prevent stroke. It is taken by mouth.

<span class="mw-page-title-main">Naringenin</span> Chemical compound

Naringenin is a flavanone from the flavonoid group of polyphenols. It is commonly found in citrus fruits, especially as the predominant flavonone in grapefruit.

<span class="mw-page-title-main">Naringin</span> Chemical compound

Naringin is a flavanone-7-O-glycoside between the flavanone naringenin and the disaccharide neohesperidose. The flavonoid naringin occurs naturally in citrus fruits, especially in grapefruit, where naringin is responsible for the fruit's bitter taste. In commercial grapefruit juice production, the enzyme naringinase can be used to remove the bitterness (debittering) created by naringin. In humans naringin is metabolized to the aglycone naringenin by naringinase present in the gut.

Grapefruit seed extract (GSE), also known as citrus seed extract, is a liquid extract derived from the seeds, pulp, and white membranes of grapefruit. GSE is prepared by grinding the grapefruit seed and juiceless pulp, then mixing with glycerin. Commercially available GSEs sold to consumers are made from the seed, pulp, and glycerin blended together. GSE is sold as a dietary supplement and is used in cosmetics.

<span class="mw-page-title-main">CYP2C9</span> Enzyme protein

Cytochrome P450 family 2 subfamily C member 9 is an enzyme protein. The enzyme is involved in the metabolism, by oxidation, of both xenobiotics, including drugs, and endogenous compounds, including fatty acids. In humans, the protein is encoded by the CYP2C9 gene. The gene is highly polymorphic, which affects the efficiency of the metabolism by the enzyme.

<span class="mw-page-title-main">CYP2C19</span> Mammalian protein found in humans

Cytochrome P450 2C19 is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some proton pump inhibitors and antiepileptic drugs. In humans, it is the CYP2C19 gene that encodes the CYP2C19 protein. CYP2C19 is a liver enzyme that acts on at least 10% of drugs in current clinical use, most notably the antiplatelet treatment clopidogrel (Plavix), drugs that treat pain associated with ulcers, such as omeprazole, antiseizure drugs such as mephenytoin, the antimalarial proguanil, and the anxiolytic diazepam.

Synergistic enhancers of antiretrovirals usually do not possess any antiretroviral properties alone, but when they are taken concurrently with antiretroviral drugs they enhance the effect of that drug.

The erythromycin breath test (ERMBT) is a method used to measure metabolism (oxidation and elimination from the system) by a part of the cytochrome P450 system. Erythromycin produces 14CO2, and this 14CO2 can be measured to study drugs that interact with the cytochrome P450 system. Erythromycin is tagged with carbon-14 and given as an intravenous injection; after 20 minutes the subject blows up a balloon and the carbon dioxide exhaled that is tagged with carbon-14 shows the activity of the CYP3A4 isoenzyme on the erythromycin. ERMBT can be used to determine how drugs that the CYP3A4 isoenzyme metabolizes will function in a given individual. The ERMBT has been widely used and verified as a reliable method for measuring CYP3A activity in real time. Its non-invasive nature makes it useful for researching drug interactions and personalizing medicine dose for drugs metabolized by CYP3A. However, its results can vary in different clinical circumstances, emphasizing the difficulty of properly predicting drug metabolism and release.

<span class="mw-page-title-main">Bergamottin</span> Chemical compound

Bergamottin (5-geranoxypsoralen) is a natural furanocoumarin found in the pulp of pomelos and grapefruits. It is also found in the peel and pulp of the bergamot orange, from which it was first isolated and from which its name is derived.

<span class="mw-page-title-main">Racecadotril</span> Chemical compound

Racecadotril, also known as acetorphan, is an antidiarrheal medication which acts as a peripheral enkephalinase inhibitor. Unlike other opioid medications used to treat diarrhea, which reduce intestinal motility, racecadotril has an antisecretory effect — it reduces the secretion of water and electrolytes into the intestine. It is available in France and other European countries as well as most of South America and some South East Asian countries, but not in the United States. It is sold under the tradename Hidrasec, among others. Thiorphan is the active metabolite of racecadotril, which exerts the bulk of its inhibitory actions on enkephalinases.

<span class="mw-page-title-main">Cobicistat</span> Chemical compound

Cobicistat, sold under the brand name Tybost, is a medication for use in the treatment of human immunodeficiency virus infection (HIV/AIDS). Its major mechanism of action is through the inhibition of human CYP3A proteins.

<span class="mw-page-title-main">6',7'-Dihydroxybergamottin</span> Chemical compound

6',7'-Dihydroxybergamottin is a natural furanocoumarin found in pomelos, grapefruits, and sour oranges, in both the peel and the pulp. Along with the chemically related compound bergamottin, it is believed to be responsible for a number of grapefruit–drug interactions, in which the consumption of citrus containing one or both of these compounds affects the metabolism of a variety of pharmaceutical drugs.

In biochemistry, cytochrome P450 enzymes have been identified in all kingdoms of life: animals, plants, fungi, protists, bacteria, and archaea, as well as in viruses. As of 2018, more than 300,000 distinct CYP proteins are known.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 12 Bailey, D. G.; Dresser, G.; Arnold, J. M. O. (2013). "Grapefruit-medication interactions: Forbidden fruit or avoidable consequences?". Canadian Medical Association Journal. 185 (4): 309–316. doi:10.1503/cmaj.120951. PMC   3589309 . PMID   23184849.
  2. 1 2 3 4 Bailey, D.G.; Dresser, G.K.; Bend, J.R. (June 2003). "Bergamottin, lime juice, and red wine as inhibitors of cytochrome P450 3a4 activity: comparison with grapefruit juice". Clinical Pharmacology & Therapeutics. 73 (6): 529–537. doi:10.1016/S0009-9236(03)00051-1. PMID   12811362. S2CID   45359353.
  3. 1 2 Gallagher, James (26 November 2012). "Grapefruit and pills mix warning". BBC News.
  4. 1 2 Chen, M.; Zhou, S. Y.; Fabriaga, E.; Zhang, P. H.; Zhou, Q. (April 2018). "Food–drug interactions precipitated by fruit juices other than grapefruit juice: An update review". J Food Drug Anal. 26 (2S): S61–S71. doi: 10.1016/j.jfda.2018.01.009 . PMC   9326888 . PMID   29703387.
  5. 1 2 3 Greenblatt DJ, von Moltke LL, Harmatz JS, et al. (August 2003). "Time course of recovery of cytochrome p450 3A function after single doses of grapefruit juice". Clinical Pharmacology and Therapeutics. 74 (2): 121–9. doi:10.1016/S0009-9236(03)00118-8. PMID   12891222. S2CID   21070191.
  6. 1 2 Mitchell, Steve (19 February 2016). "Why Grapefruit and Medication Can Be a Dangerous Mix". Consumer Reports. Retrieved 4 May 2016.
  7. 1 2 3 Hanley MK, Cancalon P, Widmer WW, Greenblatt DJ (2011). "The effect of grapefruit juice on drug disposition". Expert Opinion on Drug Metabolism & Toxicology . 7 (3): 267–286. doi:10.1517/17425255.2011.553189. PMC   3071161 . PMID   21254874.
  8. ↑ Ivey KL, Jensen MK, Rimm EB (2017). "Association of flavonoid-rich foods and flavonoids with risk of all-cause mortality". British Journal of Nutrition . 117 (10): 470–1477. doi:10.1017/S0007114517001325. PMC   7233415 . PMID   28606222.
  9. 1 2 Bailey, D. G.; Spence, J. D.; Munoz, C.; Arnold, J. M. (1991). "Interaction of citrus juices with felodipine and nifedipine". The Lancet . 337 (8736): 268–269. doi:10.1016/0140-6736(91)90872-m. PMID   1671113. S2CID   37137655.
  10. ↑ Bailey, David G.; Malcolm, J.; Arnold, O.; David Spence, J. (4 January 2002). "Grapefruit juice–drug interactions". British Journal of Clinical Pharmacology. 46 (2): 101–110. doi:10.1046/j.1365-2125.1998.00764.x. PMC   1873672 . PMID   9723817.
  11. 1 2 3 4 5 Saito, Mitsuo; Hirata-Koizumi, Mutsuko; Matsumoto, Mariko; Urano, Tsutomu; Hasegawa, Ryuichi (2005). "Undesirable effects of citrus juice on the pharmacokinetics of drugs: focus on recent studies". Drug Safety. 28 (8): 677–694. doi:10.2165/00002018-200528080-00003. PMID   16048354. S2CID   23222717.
  12. 1 2 3 4 "Fruit juice 'could affect drugs'". BBC News. 20 August 2008.
  13. ↑ "Dr. David Bailey finds new reason to avoid fruit juices when taking drugs". Western University, Canada. 20 August 2008. Archived from the original on 3 December 2012.
  14. ↑ Fujita, Tadashi; Kawase, Atsushi; Niwa, Toshiro; Tomohiro, Norimichi; Masuda, Megumi; Matsuda, Hideaki; Iwaki, Masahiro (2008). "Comparative Evaluation of 12 Immature Citrus Fruit Extracts for the Inhibition of Cytochrome P450 Isoform Activities". Biological and Pharmaceutical Bulletin. 31 (5): 925–930. doi: 10.1248/bpb.31.925 . PMID   18451520.
  15. 1 2 Edwards, D. J.; Bernier, S. M. (1996). "Naringin and naringenin are not the primary CYP3A inhibitors in grapefruit juice". Life Sciences. 59 (13): 1025–1030. doi:10.1016/0024-3205(96)00417-1. PMID   8809221.
  16. ↑ Calvarano M, Postorino E, Gionfriddo F, Calvarano I, Bovalo F, Calabro G (1 September 1996). "Naringin Extraction from Exhausted Bergamot Peels". Perfumer & Flavourist. Retrieved 19 August 2017.
  17. ↑ Paine, M.F.; Widmer, W.W.; Hart, H.L.; Pusek, S.N.; Beavers, K.L.; Criss, A.B.; Brown, S.S.; Thomas, B.F.; Watkins, P.B. (May 2006). "A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juice-felodipine interaction". The American Journal of Clinical Nutrition. 83 (5): 1097–105. doi: 10.1093/ajcn/83.5.1097 . PMID   16685052.
  18. ↑ Fuhr, Uwe (1998). "Drug Interactions with Grapefruit Juice: Extent, Probable Mechanism and Clinical Relevance". Drug Safety. 18 (4): 251–272. doi:10.2165/00002018-199818040-00002. ISSN   0114-5916. PMID   9565737. S2CID   24331721.
  19. 1 2 3 4 5 6 Pirmohamed, Munir (12 January 2013). "Drug-grapefruit juice interactions: Two mechanisms are clear but individual responses vary". BMJ. 346 (7890): 9. doi:10.1136/bmj.f1. PMID   23297175. S2CID   5581600.
  20. ↑ Veronese, Maria L.; Gillen, Lisa P.; Burke, Joanne P.; Dorval, Ellen P.; Hauck, Walter W.; Pequignot, Ed; Waldman, Scott A.; Greenberg, Howard E. (August 2003). "Exposure-Dependent Inhibition of Intestinal and Hepatic CYP3A4 In Vivo by Grapefruit Juice". The Journal of Clinical Pharmacology. 43 (8): 831–839. doi:10.1177/0091270003256059. PMID   12953340. S2CID   6513161.
  21. 1 2 Tassaneeyakul W, Guo LQ, Fukuda K, Ohta T, Yamazoe Y (June 2000). "Inhibition selectivity of grapefruit juice components on human cytochromes P450". Archives of Biochemistry and Biophysics. 378 (2): 356–63. doi:10.1006/abbi.2000.1835. PMID   10860553.
  22. ↑ He K, Iyer KR, Hayes RN, Sinz MW, Woolf TF, Hollenberg PF (April 1998). "Inactivation of cytochrome P450 3A4 by bergamottin, a component of grapefruit juice". Chemical Research in Toxicology . 11 (4): 252–9. doi:10.1021/tx970192k. PMID   9548795.
  23. ↑ Bailey DG, Malcolm J, Arnold O, Spence JD (August 1998). "Grapefruit juice–drug interactions". British Journal of Clinical Pharmacology. 46 (2): 101–10. doi:10.1046/j.1365-2125.1998.00764.x. PMC   1873672 . PMID   9723817.
  24. ↑ Garg SK, Kumar N, Bhargava VK, Prabhakar SK (September 1998). "Effect of grapefruit juice on carbamazepine bioavailability in patients with epilepsy". Clinical Pharmacology and Therapeutics. 64 (3): 286–8. doi: 10.1016/S0009-9236(98)90177-1 . PMID   9757152. S2CID   27490726.
  25. ↑ Bressler R (November 2006). "Grapefruit juice and drug interactions. Exploring mechanisms of this interaction and potential toxicity for certain drugs". Geriatrics. 61 (11): 12–8. PMID   17112309.
  26. 1 2 Seden K, Dickinson L, Khoo S, David D (2010). "Grapefruit-drug interactions". Drugs . 70 (18): 2373–2407. doi:10.2165/11585250-000000000-00000. PMID   21142260.
  27. 1 2 "Grapefruit Juice and Some Drugs Don't Mix". FDA. 1 July 2021. Retrieved 9 June 2024.
  28. ↑ Veronese ML, Gillen LP, Burke JP, et al. (August 2003). "Exposure-dependent inhibition of intestinal and hepatic CYP3A4 in vivo by grapefruit juice". Journal of Clinical Pharmacology. 43 (8): 831–9. doi:10.1177/0091270003256059. PMID   12953340. S2CID   6513161.
  29. ↑ Kane, Garvan C.; Lipsky, James J. (2000). "Drug–Grapefruit Juice Interactions". Mayo Clinic Proceedings. 75 (9): 933–942. doi:10.4065/75.9.933. ISSN   0025-6196. PMID   10994829.
  30. 1 2 Greenblatt, DJ; Patki, KC; von Moltke, LL; Shader, RI (2001). "Drug interactions with grapefruit juice: an update". J Clin Psychopharmacol. 21 (4): 357–9. doi:10.1097/00004714-200108000-00001. PMID   11476118.
  31. 1 2 3 Bailey, David G. (November 2010). "Fruit juice inhibition of uptake transport: a new type of food–drug interaction". British Journal of Clinical Pharmacology. 70 (5): 645–655. doi:10.1111/j.1365-2125.2010.03722.x. PMC   2997304 . PMID   21039758.
  32. 1 2 Chen, Chunxian; Yu, Qibin; Wei, Xu; Cancalon, Paul F.; Gmitter Jr., Fred G.; Belzile, F. (October 2014). "Identification of genes associated with low furanocoumarin content in grapefruit". Genome. 57 (10): 537–545. doi:10.1139/gen-2014-0164. PMID   25756876.
  33. 1 2 3 4 Curk, Franck; Ollitrault, Frédérique; Garcia-Lor, Andres; Luro, François; Navarro, Luis; Ollitrault, Patrick (2016). "Phylogenetic origin of limes and lemons revealed by cytoplasmic and nuclear markers". Annals of Botany. 11 (4): 565–583. doi:10.1093/aob/mcw005. PMC   4817432 . PMID   26944784.
  34. 1 2 3 4 Wu, Guohong Albert; Terol, Javier; Ibanez, Victoria; López-García, Antonio; Pérez-Román, Estela; Borredá, Carles; Domingo, Concha; Tadeo, Francisco R; Carbonell-Caballero, Jose; Alonso, Roberto; Curk, Franck; Du, Dongliang; Ollitrault, Patrick; Roose, Mikeal L. Roose; Dopazo, Joaquin; Gmitter Jr, Frederick G.; Rokhsar, Daniel; Talon, Manuel (2018). "Genomics of the origin and evolution of Citrus". Nature. 554 (7692): 311–316. Bibcode:2018Natur.554..311W. doi: 10.1038/nature25447 . hdl: 20.500.11939/5741 . PMID   29414943.
  35. 1 2 Curk, Franck; Ancillo, Gema; Garcia-Lor, Andres; Luro, François; Perrier, Xavier; Jacquemoud-Collet, Jean-Pierre; Navarro, Luis; Ollitrault, Patrick (December 2014). "Next generation haplotyping to decipher nuclear genomic interspecific admixture in Citrusspecies: analysis of chromosome 2". BMC Genetics. 15 (1): 152. doi: 10.1186/s12863-014-0152-1 . PMC   4302129 . PMID   25544367.
  36. 1 2 3 4 Widmer, Wilbur (31 May 2006). "One Tangerine/Grapefruit Hybrid (Tangelo) Contains Trace Amounts of Furanocoumarins at a Level Too Low To Be Associated with Grapefruit/Drug Interactions". Journal of Food Science. 70 (6): c419–c422. doi:10.1111/j.1365-2621.2005.tb11440.x.
  37. ↑ "Hybrid grapefruit safe for prescription meds". Futurity.org. 25 October 2011. Retrieved 28 January 2013.
  38. 1 2 Bakalar, Nicholas (21 March 2006). "Experts Reveal the Secret Powers of Grapefruit Juice". The New York Times. p. F6. Retrieved 21 November 2006.
  39. ↑ "Synonymy of C. reticulata at The Plant List".
  40. ↑ Larry K. Jackson and Stephen H. Futch (10 July 2018). "Robinson Tangerine". ufl.edu.
  41. ↑ "20-13.0061. Sunburst Tangerines; Classification and Standards, 20-13. Market Classification, Maturity Standards And Processing Or Packing Restrictions For Hybrids, D20. Departmental, 20. Department of Citrus, Florida Administrative Code". eLaws, Department of Citrus, State of Florida. Retrieved 14 May 2015.
  42. 1 2 Andrade, Chittaranjan (24 November 2014). "Fruit Juice, Organic Anion Transporting Polypeptides, and Drug Interactions in Psychiatry". The Journal of Clinical Psychiatry. 75 (11): e1323–e1325. doi: 10.4088/JCP.14f09572 . PMID   25470100.
  43. ↑ Petric, Zvonimir; Žuntar, Irena; Putnik, Predrag; Bursać Kovačević, Danijela (24 December 2020). "Food–Drug Interactions with Fruit Juices". Foods. 10 (1): 33. doi: 10.3390/foods10010033 . PMC   7823305 . PMID   33374399.
  44. 1 2 Andrade, Chittaranjan (15 April 2014). "Potentially Significant Versus Clinically Significant Drug Interactions: Pomegranate Juice as a Case in Point". The Journal of Clinical Psychiatry. 75 (4): e292–e293. doi: 10.4088/JCP.14f09112 . PMID   24813412.
  45. ↑ Rabin, Roni Caryn (17 December 2012). "Grapefruit Is a Culprit in More Drug Reactions". The New York Times.
  46. 1 2 Gross AS, Goh YD, Addison RS, Shenfield GM (April 1999). "Influence of grapefruit juice on cisapride pharmacokinetics". Clinical Pharmacology and Therapeutics. 65 (4): 395–401. doi:10.1016/S0009-9236(99)70133-5. PMID   10223776. S2CID   8445735.
  47. ↑ "Wake Forest Baptist Medical Center" (PDF). wakehealth.edu. Archived from the original (PDF) on 5 August 2017. Retrieved 4 May 2016.
  48. ↑ Musmul, A.; Cingi, M. Ipek; Boydaĝ, B. S.; Aktan, Yasemın; Özdemir, Murat (1998). "Interaction between grapefruit juice and diazepam in humans". European Journal of Drug Metabolism and Pharmacokinetics. 23 (1): 55–59. doi:10.1007/BF03189827. PMID   9625273. S2CID   9055484.
  49. ↑ "Drug Interactions Checker - Medscape Drug Reference Database". reference.medscape.com. Retrieved 6 March 2019.
  50. ↑ Tanaka, E. (October 1999). "Clinically significant pharmacokinetic drug interactions with benzodiazepines". Journal of Clinical Pharmacy and Therapeutics. 24 (5): 347–355. doi: 10.1046/j.1365-2710.1999.00247.x . PMID   10583697. S2CID   22229823.
  51. ↑ Sugimoto K, Araki N, Ohmori M, et al. (March 2006). "Interaction between grapefruit juice and hypnotic drugs: comparison of triazolam and quazepam". European Journal of Clinical Pharmacology. 62 (3): 209–15. doi:10.1007/s00228-005-0071-1. PMID   16416305. S2CID   32616279.
  52. ↑ "Ritonavir (Norvir)". HIV InSite. UCSF. 18 October 2006. Retrieved 12 March 2008.[ failed verification ]
  53. ↑ Lee AJ, Chan WK, Harralson AF, Buffum J, Bui BC (November 1999). "The effects of grapefruit juice on sertraline metabolism: an in vitro and in vivo study". Clinical Therapeutics. 21 (11): 1890–9. doi:10.1016/S0149-2918(00)86737-5. PMID   10890261.
  54. ↑ Pillai, Unnikrishnan; Muzaffar, Jameel; Sen, Sandeep; Yancey, Abigail (2009). "Grapefruit Juice and Verapamil: A Toxic Cocktail". Southern Medical Journal. 102 (3): 308–309. doi:10.1097/smj.0b013e3181928f81. PMID   19204629. S2CID   41147941 . Retrieved 22 January 2017.
  55. ↑ Fuhr, Uwe (1998). "Drug Interactions with Grapefruit Juice". Drug Safety. 18 (4): 251–272. doi:10.2165/00002018-199818040-00002. PMID   9565737. S2CID   24331721.
  56. ↑ Wu D, Otton SV, Inaba T, Kalow W, Sellers EM (June 1997). "Interactions of amphetamine analogs with human liver CYP2D6". Biochemical Pharmacology. 53 (11): 1605–12. doi:10.1016/S0006-2952(97)00014-2. PMID   9264312.
  57. ↑ Preissner S, Kroll K, Dunkel M, et al. (January 2010). "SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP–drug interactions". Nucleic Acids Research. 38 (Database issue): D237–43. doi:10.1093/nar/gkp970. PMC   2808967 . PMID   19934256.
  58. ↑ Shah A, Kumar S, Simon SD, Singh DP, Kumar A (2013). "HIV gp120- and methamphetamine-mediated oxidative stress induces astrocyte apoptosis via cytochrome P450 2E1". Cell Death & Disease. 4 (10): e850. doi:10.1038/cddis.2013.374. PMC   3824683 . PMID   24113184.
  59. ↑ "Metabolism/ Metabolites of amphetamines interacting with The Cytochrome P450 CYP2D6 enzyme". U.S. National Library of Medicine.[ verification needed ]
  60. 1 2 Lilja JJ, Kivistö KT, Neuvonen PJ (August 1999). "Grapefruit juice increases serum concentrations of atorvastatin and has no effect on pravastatin". Clinical Pharmacology and Therapeutics. 66 (2): 118–27. doi:10.1053/cp.1999.v66.100453001. PMID   10460065. S2CID   8103490.
  61. 1 2 3 4 5 6 7 8 9 Bailey DG, Dresser GK (2004). "Interactions between grapefruit juice and cardiovascular drugs". American Journal of Cardiovascular Drugs. 4 (5): 281–97. doi:10.2165/00129784-200404050-00002. PMID   15449971. S2CID   11525439.
  62. ↑ Bressler R (2006). "Grapefruit juice and drug interactions. Exploring mechanisms of this interaction and potential toxicity for certain drugs". Geriatrics. 61 (11): 12–18. PMID   17112309.
  63. ↑ Jetter A, Kinzig-Schippers M, Walchner-Bonjean M, et al. (January 2002). "Effects of grapefruit juice on the pharmacokinetics of sildenafil". Clinical Pharmacology and Therapeutics. 71 (1): 21–9. doi:10.1067/mcp.2002.121236. PMID   11823754. S2CID   40447204.
  64. ↑ Dasgupta A, Reyes MA, Risin SA, Actor JK (December 2008). "Interaction of white and pink grapefruit juice with acetaminophen (paracetamol) in vivo in mice". Journal of Medicinal Food. 11 (4): 795–8. doi:10.1089/jmf.2008.0059. PMID   19053875.
  65. ↑ Qinna, Nidal A.; Ismail, Obbei A.; Alhussainy, Tawfiq M.; Idkaidek, Nasir M.; Arafat, Tawfiq A. (1 April 2016). "Evidence of reduced oral bioavailability of paracetamol in rats following multiple ingestion of grapefruit juice". European Journal of Drug Metabolism and Pharmacokinetics. 41 (2): 187–195. doi:10.1007/s13318-014-0251-4. PMID   25547640. S2CID   18180270.
  66. ↑ Samojlik, I.; Rasković, A.; Daković-Svajcer, K.; Mikov, M.; Jakovljević, V. (1 July 1999). "The effect of paracetamol on peritoneal reflex after single and multiple grapefruit ingestion". Experimental and Toxicologic Pathology. 51 (4–5): 418–420. doi:10.1016/S0940-2993(99)80032-3. PMID   10445408.
  67. ↑ Elkader A, Sproule B (2005). "Buprenorphine: clinical pharmacokinetics in the treatment of opioid dependence". Clinical Pharmacokinetics. 44 (7): 661–80. doi:10.2165/00003088-200544070-00001. PMID   15966752. S2CID   25521902.
  68. ↑ Lilja JJ, Kivistö KT, Backman JT, Lamberg TS, Neuvonen PJ (December 1998). "Grapefruit juice substantially increases plasma concentrations of buspirone". Clinical Pharmacology and Therapeutics. 64 (6): 655–60. doi:10.1016/S0009-9236(98)90056-X. PMID   9871430. S2CID   22009095.
  69. ↑ Smith, Howard S. (1 July 2009). "Opioid Metabolism". Mayo Clinic Proceedings. 84 (7): 613–624. doi:10.4065/84.7.613. PMC   2704133 . PMID   19567715.
  70. ↑ Paine MF, Widmer WW, Pusek SN, et al. (April 2008). "Further characterization of a furanocoumarin-free grapefruit juice on drug disposition: studies with cyclosporine". The American Journal of Clinical Nutrition. 87 (4): 863–71. doi: 10.1093/ajcn/87.4.863 . PMID   18400708.
  71. ↑ "HIGHLIGHTS OF PRESCRIBING INFORMATION" (PDF). Gene. Retrieved 28 January 2013.
  72. ↑ Burnett, Bruce (1 September 2014). "Exemestane (Aromasin)". Macmillan Cancer Support. Retrieved 17 July 2017.
  73. ↑ Dresser GK, Kim RB, Bailey DG (March 2005). "Effect of grapefruit juice volume on the reduction of fexofenadine bioavailability: possible role of organic anion transporting polypeptides". Clinical Pharmacology and Therapeutics. 77 (3): 170–7. doi:10.1016/j.clpt.2004.10.005. PMID   15735611. S2CID   24716662.
  74. ↑ Yael Waknine (1 January 2007). "FDA Safety Changes: Allegra, Cymbalta, Concerta". Medscape Medical News.
  75. ↑ Hori H, Yoshimura R, Ueda N, et al. (August 2003). "Grapefruit juice-fluvoxamine interaction--is it risky or not?". Journal of Clinical Psychopharmacology. 23 (4): 422–4. doi:10.1097/01.jcp.0000085423.74359.f2. PMID   12920426. S2CID   30993451.
  76. ↑ Jhaveri, Limca. "Novartis Answers About Gleevec". GIST Support International. Archived from the original on 23 January 2011. Retrieved 31 December 2010.
  77. ↑ Peltoniemi, Marko A.; Saari, Teijo I.; Hagelberg, Nora M.; Laine, Kari; Neuvonen, Pertti J.; Olkkola, Klaus T. (June 2012). "S-ketamine concentrations are greatly increased by grapefruit juice". European Journal of Clinical Pharmacology. 68 (6): 979–986. doi:10.1007/s00228-012-1214-9. ISSN   1432-1041. PMID   22286159. S2CID   15742712.
  78. ↑ Lilja JJ, Laitinen K, Neuvonen PJ (September 2005). "Effects of grapefruit juice on the absorption of levothyroxine". British Journal of Clinical Pharmacology. 60 (3): 337–41. doi:10.1111/j.1365-2125.2005.02433.x. PMC   1884777 . PMID   16120075.
  79. ↑ Benmebarek M, Devaud C, Gex-Fabry M, et al. (July 2004). "Effects of grapefruit juice on the pharmacokinetics of the enantiomers of methadone". Clinical Pharmacology and Therapeutics. 76 (1): 55–63. doi:10.1016/j.clpt.2004.03.007. PMID   15229464. S2CID   25693476.
  80. ↑ Mouly S, Paine MF (August 2001). "Effect of grapefruit juice on the disposition of omeprazole". British Journal of Clinical Pharmacology. 52 (2): 216–7. doi:10.1111/j.1365-2125.1978.00999.pp.x. PMC   2014525 . PMID   11488783.
  81. ↑ Nieminen, Tuija H.; Hagelberg, Nora M.; Saari, Teijo I.; Neuvonen, Mikko; Neuvonen, Pertti J.; Laine, Kari; Olkkola, Klaus T. (1 October 2010). "Grapefruit juice enhances the exposure to oral oxycodone". Basic & Clinical Pharmacology & Toxicology. 107 (4): 782–788. doi: 10.1111/j.1742-7843.2010.00582.x . PMID   20406214.
  82. ↑ "Grapefruit Interactions" (PDF). healthCentral. Archived from the original (PDF) on 18 November 2012. Retrieved 28 January 2013.
  83. ↑ Cohen E, Wu K, Ratain MJ (2012). "Phase I studies of sirolimus alone or in combination with pharmacokinetic modulators in advanced cancer patients". Clinical Cancer Research . 18 (17): 4785–4793. doi:10.1158/1078-0432.CCR-12-0110. PMC   4410974 . PMID   22872575.
  84. ↑ Beverage JN, Sissung TM, Sion AM, Danesi R, Figg WD (September 2007). "CYP2D6 polymorphisms and the impact on tamoxifen therapy". Journal of Pharmaceutical Sciences. 96 (9): 2224–31. doi:10.1002/jps.20892. PMID   17518364.
  85. 1 2 "Grapefruit and medication: A cautionary note". Harvard Medical School Family Health Guide. February 2006. Retrieved 28 January 2013.
  86. ↑ Jellin J.M., et al. Pharmacist's Letter/Prescriber's Letter of Natural Medicines Comprehensive Database. 7th ed. Stockton, CA: Therapeutic Research Faculty. 2005. 626-629
  87. ↑ "Corlanor (ivabradine) dose, indications, adverse effects, interactions..." PDR.net.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.