Diltiazem has been found to produce no interaction with grapefruit juice in a single study Sigusch et al, , and further investigations are needed. The calcium channel antagonists exhibiting the interaction have demonstrated altered clinical parameters, including increased adverse effects, when administered with grapefruit juice. Therefore, it is advisable to avoid this combination, especially with the more affected agents — felodipine, nisoldipine and nicardipine.
The benzodiazepines are the most important and widely used family of sedative—hypnotics, acting on inhibitory receptors in the CNS. Few of them are CYP3A4 substrates at a certain level, and a potential interaction with grapefruit juice may cause a deviation from the standard dose, producing an undesired increase in the CNS-depressant effects.
A single glass of regular strength grapefruit juice has been shown to increase by more than 3-fold the AUC of diazepam Ozdemir et al, However, grapefruit juice does not alter the pharmacokinetics of alprazolam, even after repeated ingestions, presumably due to its high bioavailability Yasui et al, As to the clinical effect, the available data are more ambiguous.
A performance decrease in psychometric tests of human subjects undergoing treatment with Midazolam and grapefruit juice compared to water has been observed in one pharmacodynamic study Kupferschmidt et al, On the other hand, in a different study, hardly any increase in the clinical effects of midazolam and triazolam has been detected following grapefruit juice intake Vanakoski et al, The reported increase in bioavailability of these agents may be clinically significant, especially in patients possessing other risk factors for decreased first pass elimination such as liver disease and old age.
Another CNS depressant showing an interaction with grapefruit juice is the anticonvulsant agent carbamazepine. Grapefruit juice has also been observed to increase substantially the plasma concentration of buspirone, a nonbenzodiazepine hypnotic with a very low bioavailability due to extensive metabolism by CYP3A4 Lilja et al, Such a dramatic increase could result in toxic levels of buspirone.
Hence, avoiding this combination should be advised. Sertralin is a serotonin selective reuptake inhibitor that is widely used in the treatment of depression and anxiety disorders, and is metabolized mainly by CYP3A4. These results were consistent with in vitro inhibition of sertralin metabolism Lee et al, The clinical relevance of the interaction has not been assessed.
The statins are an important class of cholesterol lowering medications that act by competitive inhibition of 3-hydroxymethylglutaryl coenzyme A HMG-CoA reductase. Statins undergo metabolism through CYP3A4 to various degrees. Simvastatin and lovastatin are inactive lactones that undergo hydrolysis by esterases to form the active simvastatin acid and lovastatin acid, respectively.
Inhibition of simvastatin metabolism by naringenin was demonstrated in vitro Ubeaud et al, The same regimen of grapefruit juice caused a fold increase in the AUC of lovastatin, and a five-fold increase in the AUC of lovastatin acid Figure 2 Kantola et al, Although a large amount of grapefruit juice has been used, these data can indicate that a regular amount of the juice can alter the pharmacokinetic parameters of simvastatin and lovastatin.
This trend is further supported by double AUC values for lovastatin and lova-statin acid after drinking one glass of regular strength grapefruit juice in the morning for three consecutive days followed by a dose of the medicine at the third evening Rogers et al, The AUC value of atorvastatin showed a 2. Grapefruit juice has no effect on pravastatin Lilja et al, , apparently since it is metabolized only to a limited extent by CYP3A4 Jacobsen et al, Cyclosporine is a powerful immunosuppressive agent used extensively in transplantation to prevent rejection of transplanted organs.
Cyclosporine is extensively metabolized by CYP3A4 in the gut wall of the small intestine and in the liver Kolars et al, It is also a high affinity P-gp substrate Lown et al, This alteration has been observed with the cyclosporine microemulsion formulation as well Bistrup et al, Elevated cyclosporine concentrations were reported in healthy subjects Yee et al, and in transplant patients Min et al, In pediatric renal transplant patients, concomitant grapefruit juice administration altered cyclosporine AUC, C max and elimination parameters as well Brunner et al, Grapefruit juice had no effect after intravenous administration of the drug Ducharme et al, Cyclosporine has a narrow therapeutic index, and many side effects such as nephrotoxicity, hypertension and cerebral toxicity.
Therefore, it seems necessary to advise patients treated with cyclosporine not to consume grapefruit juice during therapy. Saquinavir is a protease inhibitor, used in the treatment of human immunodeficiency virus infection.
Inhibition of saquinavir metabolism in vitro by grapefruit juice components has also demonstrated Eagling et al, Until further investigations, this combination should be avoided. Other protease inhibitors have high bioavailability, thus, interaction with grapefruit juice is unlikely to occur. Sildenafil citrate is used for the oral treatment of erectile dysfunction.
It acts by enhancing the ability of nitric oxide to inhibit phosphodiesterase type 5. Consequently, sildenafil pharmaco-kinetics becomes less predictable with grapefruit juice, and it is advisable to avoid this combination.
Cizapride, a prokinetic agent, has been used for the treatment of a number of gastrointestinal disorders. CYP3A4 is the primary mode of elimination of cisapride Bohets et al, In another study, high doses of grapefruit juice were used and similar outcomes have been reported Kivisto et al, It appears that a clinically significant outcome may arise from the combination of cizapride and grapefruit juice, and avoidance of this combination is recommended.
Terfenadine is a second generation, nonsedative, selective H 1 receptor antagonist used in the treatment of many allergic conditions. Terfenadine undergoes nearly complete pre-systemic elimination by CYP3A4 to such a broad extent and rapid kinetics that normally terfenadine cannot be detected in plasma.
The antihistaminic activity in vivo has been attributed to its carboxilic metabolites Yun et al, High levels of unmetabolized terfenadine are associated with significant cardiotoxicity such as QT prolongation and torsade de pointes Woosley et al, Administration of grapefruit juice concurrently with terfenadine significantly elevated terfenadine plasma concentrations Benton et al, ; Clifford et al, One glass of regular strength grapefruit juice was enough to produce maximum effect on terfenadine pharmacokinetics Rau et al, A y-old man who had been taking terfenadine twice daily for more than a year, collapsed and died on a day on which he had consumed two glasses of grapefruit juice.
The man was not taking erythromycin, ketoconazole, or any other drug known to affect terfenadine metabolism Spence, Thus, it seems necessary to avoid concomitant consumption of grapefruit juice and terfenadine. Amiodarone is a class III antiarrythmic agent. Its major metabolite, N -desethylamiodarone N -DEA has been shown to contribute the antiarrythmic effect, possibly to a greater extent than the parent drug Talajic et al, ; Zhou et al, The clinical implications of this finding are still unclear and need further investigation.
It is likely that more information regarding this interaction, including more drugs exhibiting the interaction, will accumulate in the future. It can be anticipated, based on the analogous mechanism, that grapefruit juice will demonstrate, at least partially, similar interactions that occur with erythromycin, ketoconazole and other macrolide antibiotics and azole antifungal agents.
It is important to notice that the whole fruit can cause the same outcomes as does the juice Bailey et al, The vast majority of the investigations regarding this interaction are characterized by a wide variability of the results among patients within each study, as well as variability between studies. The different kinds of juice used by different investigators might be a contributor for this.
Food and Drug Administration has required that some prescription and over-the-counter OTC drugs generally taken by mouth include warnings against drinking grapefruit juice or eating grapefruit while taking the drug. Here are examples of some types of drugs that grapefruit juice can cause problems interact with:.
Grapefruit juice does not affect all the drugs in the categories above. The severity of the interaction can be different depending on the person, the drug, and the amount of grapefruit juice you drink. Talk to your health care provider or pharmacist, and read any information provided with your prescription or non-prescription OTC drug to find out:. For example, if you drink a lot of grapefruit juice while taking certain statin drugs to lower cholesterol, too much of the drug may stay in your body, increasing your risk for liver and muscle damage that can lead to kidney failure.
Many drugs are broken down metabolized with the help of a vital enzyme called CYP3A4 in the small intestine. Grapefruit juice can block the action of intestinal CYP3A4, so instead of being metabolized, more of the drug enters the blood and stays in the body longer.
Statins are medicines that lower your cholesterol. Grapefruit or grapefruit juice affects some statins. Do not drink grapefruit juice if you're taking simvastatin.
Grapefruit juice increases the level of simvastatin in your blood and makes side effects more likely. Atorvastatin interacts with grapefruit juice if you drink large quantities more than 1. Currently, healthcare professionals advise it is safe to drink grapefruit juice and eat grapefruit if you're taking other types of statins.
Calcium channel blockers are medicines that relax the muscles that make up the walls of your arteries. They're used as part of the treatment of conditions such as high blood pressure hypertension and coronary heart disease. Grapefruit juice interacts with some calcium channel blockers and increases the level of the medicine in your blood.
If you're taking any of the medicines below, seek advice from your pharmacist or doctor if you wish to include grapefruit or grapefruit juice in your diet. Grapefruit juice does not affect diltiazem.
Anticoagulants are medicines that help to prevent blood clots. They're given to people at high risk of getting clots, to reduce their chances of serious conditions such as strokes and heart attacks. Do not drink grapefruit juice if you're taking warfarin. It can increase the effect of warfarin on your blood, making you bleed more easily. It's safer to drink grapefruit juice if you're taking the newer anticoagulants rivaroxaban , dabigatran , apixaban or edoxaban.
Antiplatelet medicines prevent platelets a type of blood cell from sticking together and forming blood clots.
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