How Well Do You Know the Grapefruit Drug Interaction?

Prescribers, pharmacists, direct-to-consumer advertising, and patient leaflets mention grapefruit-induced drug interactions with a variety of common medications. For example, grapefruit can increase atorvastatin (among many medications) and decrease fexofenadine levels in the body.¹ But is grapefruit special?

The most significant offending natural compound, bergamottin (named after the bergamot orange), prevents the breakdown of medications through the most numerous and often used metabolizing enzyme (CYP3A4). Medications are broken down less by this enzyme before absorption into the blood if bergamottin has been in the gut recently. This causes drug levels in the blood to rise higher than normal and cause negative reactions (eg statin-induced muscle breakdown). Bergamottin interferes with the metabolism of amphetamines through a related enzyme (CYP2D6) as well. Bergamottin affects fewer medications by preventing their pumping into the blood; these medications, such as fexofenadine, are less effective when taken with bergamottin-containing products. Either effect can have serious consequences on patient safety.

Bergamottin is in more than just grapefruit. Skincare products, perfumes, and food flavorings use its namesake the bergamot orange but consumers rarely eat the whole fruit. Oil of bergamot contains a litany of phototoxic and carcinogenic compounds, including bergamottin and psoralen, which cause redness and increase skin cancer risk after sun exposure.²

Bergamot oil contains anti-cholesterol compounds; these compounds worsen bergamottin’s statin-boosting effects.³ Earl Grey tea, certain fruit jams (e.g. containing Seville orange peels), and bergamot-flavored products (including pharmaceuticals) are often overlooked sources of bergamot oil.

Eating a whole grapefruit or drinking a cup of grapefruit juice can cause a clinically significant interaction with a host of medications. Repeated consumption has a greater effect than one exposure but certain medications’ effects are sensitive to consistent drug levels (e.g. cyclosporine).⁴ The impact of other bergamottin sources is unclear.

Research has intensified into bergamot orange’s cholesterol-lowering and anti-inflammatory effects. The combination of bergamot-based complementary and alternative medicine with prescriptions would increase the frequency of unintended drug interactions.

One Italian team found bergamot extract reduced plasma lipids and improved patient lipoprotein profile at follow-up after six months use. The probable cholesterol-lowering compounds overlap with bergamot’s drug-interacting compounds.⁵

This team compared fasting lipid panels and carotid arterial wall thickness ultrasound findings at baseline and six months later of 80 patients with moderate hypercholesterolemia. The fasting lipid panels directly measured total cholesterol, triglycerides, and high density lipoprotein cholesterol (HDL). The researchers indirectly calculated low density lipoprotein cholesterol (LDL) with the Friedewald formula.

Patient total cholesterol, triglycerides, low density lipoprotein, and carotid wall thickness decreased after six months of bergamot extract use. The improvement in vascular wall thickness strengthens the laboratory findings’ real world applicability. Plaques in the carotid artery can precipitate strokes directly and the state of the easily viewed carotid acts as a surrogate for the severity of cholesterol deposits throughout the body.

The authors posit bergamot extract increases fatty acid oxidation, LDL receptor expression and sequestration. These mechanisms join together to reduce triglycerides and cholesterol in the blood respectively. Statins share the same LDL receptor mechanism and this may explain the particularly troublesome interaction with atorvastatin.

Bergamot extract has anti-inflammatory effects, including oxidative stress reducing antioxidant properties, under review by a second Italian team of researchers. Anti-inflammatory agents and antioxidants lessen the risk of developing lifestyle disorders such as type 2 diabetes and certain cancers.

The team identified 8 flavonoids in bergamot juice and that bergamot oil has 4 coumarins (e.g. bergamottin) and 4 terpenes. The flavonoids scavenge free radicals, chelate metal ions, and strengthen cellular protections against reactive oxygen species in vitro.

Bergamot peel extract reduces immune-mediated oxidative stress and vascular endothelium cell death. This mechanism may promise curtailed plaque rupture (and therefore heart attack and stroke risk). Bergamot extract inhibits a T-cell-driven inflammatory process in Alzheimer’s disease. However, the precise initiator and driver(s) of Alzheimer’s disease are unclear. Animal inflammatory bowel disease models suggest bergamot reduces auto-immune damage to the gut lining.⁶ These early findings will encourage clinical studies in variety of conditions including cardiovascular conditions commonly treated with interacting statins.

An understanding of why grapefruit and certain medication interact exposes the related risk of well-known consumer products and emerging complementary and alternative medicines. Patients may avoid these interacting products or request a switch to a non-interacting medication if possible. Awareness is the primary barrier to successful avoidance therefore patient education by prescribers and pharmacists should include mention of these products.

References

• Grapefruit Juice and Medicine May Not Mix. Food and Drug Administration web site. https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm292276.htm. Published February 22, 2012. Updated January 27, 2014. Accessed February 21, 2017.
• Bergamot. WebMD website. http://www.webmd.com/vitamins-supplements/ingredientmono-142-BERGAMOT%20OIL.aspx?activeIngredientId= 142&activeIngredientName=BERGAMOT%20OIL. Accessed February 21, 2017.
• Di Donna L, De Luca G, Mazzotti F, et al. Statin-like principles of bergamot fruit (Citrus bergamia): isolation of 3-hydroxymethylglutaryl flavonoid glycosides. J Nat Prod. 2009; 72(7): 1352—1354. doi: 10.1021/np900096w.
• Mixing grapefruit with medicines. NPS MedicineWise web site. http://www.nps.org.au/publications/consumer/medicinewise-living/2012/mixing-grapefruit-with-medicines. Published July 18, 2014. Accessed February 21, 2017.
• Toth PP, Patti AM, Nikolic D, et al. Bergamot reduces plasma lipids, atherogenic small dense LDL, and subclinical atherosclerosis in subjects with moderate hypercholesterolemia: a 6 months prospective study. Pharmacol. 2016; 6: 299. doi:10.3389/fphar.2015.00299
• Ferlazzo N, Cirmi S, Calapai G, et al. Anti-inflammatory activity of Citrus bergamia derivatives: where do we stand? Molecules. 2016; 21: 1273. doi:10.3390/molecules21101273.