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MAY 2013 GRAPEFRUIT INTERACTIONS G rapefruit and other juices can interact with many medicines, affecting either the efficacy or causing adverse effects. Although the potential for drug-interactions involving grapefruit juice has been known for over twenty years, a recent report from Canadian researchers in the Canadian Medical Association Journal increased the awareness of grapefruit drug-interactions with more than 85 medications now known to interact with grapefruit juice. The report noted that the number of medications identified as interacting with grapefruit has doubled with potentially fatal interactions increasing from 17 to 43 in the past four years (2008 – 2012). The researchers identified 43 medications which can cause serious side effects. Serious side effects have occurred when certain medicines are taken with grapefruit, including: ■■ complete heart block (resulting in a very slow heart beat) ■■ torsade de pointes (rapid heartbeats that can lead to sudden death) ■■ rhabdomyolysis (severe damage to skeletal muscle that can lead to kidney damage) ■■ nephrotoxicity (kidney damage) ■■ myelotoxicity (damage to bone marrow) ■■ respiratory depression (reduced or slowed breathing). Commonly used medications implicated include certain cholesterol-lowering medications, blood pressure medications, cancer treatments, immunosuppressant agents, and some antibiotics and antivirals. Examples include (note this list is not exhaustive): ■■ Atorvastatin, simvastatin ■■ Colchicine ■■ Amiodarone ■■ Erythromycin ■■ Cyclosporin ■■ Domperidone (Motilium) ■■ Eplerenone (Inspra) © Manrex Pty Ltd (ABN: 63 074 388 088) t/as Webstercare - 2013 ■■ ■■ ■■ ■■ ■■ alcium channel blockers e.g. felodipine, losartan, C nifedipine, verapamil, lercanidipine Anticoagulants e.g. rivaroxaban (Xarelto) Platelet aggregation inhibitor e.g. ticagrelor (Brilinta), clopidogrel (Plavix, Iscover) Sildenafil (Viagra), vardenafil (Levitra) Urinary tract agents e.g. darifenacin (Enablex), Solifenacin (Vesicare), tamsulosin (Flomaxtra) Mechanism of action Grapefruit drug-interactions occur due to interference with the liver enzyme known as cytochrome P450 3A4 (CYP3A4). This enzyme is responsible for the metabolism of about 50% of all medicines. With these enzymes inhibited by grapefruit, medication concentrations can increase rapidly and lead to potentially toxic effects. CYP3A4 is located in epithelial cells (enterocytes) lining the small intestines and colon, and in the parenchymal cells of the liver (hepatocytes). The substance in grapefruit involved in this interaction are the furanocoumarins, specifically 6,7-dihydroxybergamottin. Freshly squeezed juice, canned or bottled juice and whole fruit can cause an interaction. Near maximal inhibition of gut CYP3A4 occurs with just one glass of grapefruit juice or one whole grapefruit. The potential for these drug interactions can exist for 48 to 72 hours after the last exposure to grapefruit juice. This is because a new enzyme has to be synthesised in the gut wall, which takes around 3 days. As a result, medications which interact with grapefruit can’t just be separated by a few hours to avoid the potential for these effects. Residents taking medications known to significantly interact with grapefruit should avoid grapefruit and grapefruit juice entirely. In many cases alternative medications may be available for those patients who do not want to stop consuming grapefruit. GRAPEFRUIT INTERACTIONS Examples of grapefruit interactions Blood levels of ticagrelor are more than doubled by grapefruit juice, leading to an enhanced and prolonged antiplatelet effect. The combination of grapefruit juice and amiodarone in one case led to bradycardia and marked QT prolongation associated with ventricular arrhythmias, including an episode of torsade de pointes requiring immediate electrical cardioversion. This lady had been drinking about one litre of juice daily. Felodipine combined with just one glass of grapefruit had an average systemic drug concentration that was 3-fold that seen with water. The systemic concentration of cholesterol-lowering drug simvastatin is increased by 330% when combined with a 200mL glass of grapefruit juice once a day for 3 days, compared with water. This can lead to muscle weakness and pain (myopathy) or rhabdomylosis with life-threatening muscle injury and possible kidney failure. Not all statins interact with grapefruit – only simvastatin and to a lesser extent atorvastatin. Pravastatin, fluvastatin and rosuvastatin do not interact. Apple and orange juice interactions Fruit juices may also decrease the oral absorption of drugs by inhibiting intestinal drug transport. Grapefruit, apple juice and orange juice are potent inhibitors of organic anion-transporting polypeptides (OATP). OATPs transport drugs across the cell membrane, particularly in the liver and kidney. This interaction with fruit juices diminishes the oral drug bioavailability (fraction of an administered dose of unchanged drug that reaches the systemic circulation) through inhibition of uptake transport, thereby reducing the effectiveness of the medication. The constituent in grapefruit which inhibits OATP is the bioflavonoid naringin. For example, routine intake of thyroxine with grapefruit or orange juice might result in a reduction in blood concentration sufficient to induce under-treatment. Apple and orange juice can decrease the amount of atenolol available from a dose. Orange juice reduces the blood concentration of a dose of atenolol by about half. About three glasses (600mL) of apple juice taken over one and a half hours can reduce the amount of atenolol in the blood stream by over half (58%). This effect with apple juice appears to be enhanced with larger amounts of apple juice. Ingestion of 1200 mL apple juice consumed over 3 hours reduces the amount of atenolol by 82%. Apple juice reduces the amount of the antihistamine fexofenadine (Telfast) reaching the blood stream by three- © Manrex Pty Ltd (ABN: 63 074 388 088) t/as Webstercare - 2013 quarters. Grapefruit juice reduces it by approximately one-half. These interactions can lead to a lack of effect of the antihistamine. In contrast to CYP3A4 interactions, OATP-mediated fruit juice interactions may potentially be avoided by separating medicine and juice consumption by at least four hours. Other fruit interactions The effect is not limited to grapefruit. Other less-sweet citrus fruits such as Seville oranges (often used in marmalades), limes, star fruit, tangelos and pomelos also contain the active ingredients furanocoumarins. Management of interactions It is not practical to eat a consistent amount of fruit or juice to avoid interactions with grapefruit. Fruit species, geographical origin, maturity, manufacturing process, storage conditions, and seasonal variability will all affect the amount of furanocoumarins. People who take medicines that may interact with grapefruit are usually advised not to eat grapefruit or drink grapefruit juice at all. Interactions with grapefruit, apple and orange juice by the OATP mechanism (e.g. thyroxine, atenolol) can be managed by separating the juice and medication by at least 4 hours. A Residential Medication Management Review (RMMR) by a pharmacist will help identify medications known to interact with grapefruit and provide recommendations for alternate medications. For more information see http://www.nps.org.au/ publications/consumer/medicinewise-living/2012/ mixing-grapefruit-with-medicines References Br J Clin Pharmacol 2010;70(5):645-655. Br J Clin Pharmacol 2004;58:56-60. Br J Clin Pharmacol 2013;75(1):172-9. Eur J Clin Pharmacol 2005;61:337-40. Clinical Pharmacology & Therapeutics 2007;81:362-370. Am J Emerg Med 2012;30:248.e5-e8.