A spoonful of grapefruit does not help the medicine go down, it turns out. And in some cases, it could prove deadly.

Researchers are now finding an increasing number of instances of dangerous drug interactions between various medications and grapefruit. The more serious side effects range from internal bleeding to kidney failure, heart abnormalities and sudden death. (A full list of susceptible drugs appears at the end of this article.)

In a paper published Monday in the Canadian Medical Association Journal, three Ontario-based researchers review recent case studies and articles examining grapefruit-drug interactions and call upon doctors to be aware of the potentially dangerous mixture of certain drugs and citrus fruits.

"Unless health care professionals are aware of the possibility that the adverse event they are seeing might have an origin in the recent addition of grapefruit to the patient's diet, it is very unlikely that they will investigate it," the authors wrote. "In addition, the patient may not volunteer this information. Thus, we contend that there remains a lack of knowledge about this interaction in the general healthcare community."

Between 2008 and 2012, the introduction of new medications and new formulations of existing drugs increased the number of substances with the potential for seriously dangerous interactions with grapefruit from 17 to 43. Overall, more than 85 drugs in circulation have the potential to interact with the fruit.

There are several factors common to drugs that interact with grapefruit: They are all taken by mouth, the have low to intermediate bioavailability -- meaning that only a fraction of the drug will circulate in the bloodstream, with the rest digested -- and all of them are broken down by an enzyme called cytochrome P450 3A4, also known as CYP3A4.

Grapefruit also interacts with CYP3A4 through chemicals called furanocoumarins, which inactivate CYP3A4. Turning off the enzyme means that less of the drug is absorbed by the small intestine and liver, so a person gets a much higher dose of the drug than expected, leading to accidental overdoses of the medication.

Affected drugs range from anticancer drugs like Nilotinib, sold under the brand name Tasigna, to the bladder medication Solifenacin, also known as Vesicare. The lower a drug's normal bioavailability, the greater the possible consequences of a grapefruit interaction. Elderly people seem to be more at risk for dangerous interactions -- though this may just be because older people tend to both buy more grapefruit and take more medications, the authors say.

All forms of grapefruit, including whole fruit, juice and frozen concentrate, contain the enzyme-inactivating chemicals.

“One whole grapefruit or 200 [milliliters] of grapefruit juice is sufficient to cause clinically relevant increased systemic drug concentration and subsequent adverse effects,” the authors wrote.

The effect of the grapefruit also lingers. According to the authors, the maximum possible drug interaction occurs four hours after a glass of grapefruit juice. Twenty-four hours after the juice is consumed, there is still the potential for drug interaction, though it is at a quarter of the maximum.

Other fruits like limes, pomelos and seville oranges -- often used to make marmalade -- also interact with the enzyme in the way that grapefruits do. Most sweet oranges, including navel and valencia varieties, are not dangerous because they do not contain furanocoumarins.

If you're unsure about possible grapefruit interactions with your medication, ask your doctor or consult the list below to see if your drug appears.

“The current trend of increasing numbers of newly marketed grapefruit-affected drugs possessing substantial adverse clinical effects necessitates an understanding of this interaction and the application of this knowledge for the safe and effective use of drugs in general practice,” the authors wrote.

So, if you're still unsure about your medication, it may be best to switch to orange juice for the time being.

SOURCE: Bailey et al. “Grapefruit-medication interactions. Forbidden fruit or avoidable consequences?” CMAJ published ahead of print 26 November 2012.

SELECT LIST OF DRUGS WITH GRAPEFRUIT INTERACTION POTENTIAL (according to Bailey et al.):

Anti-cancer drugs: Crizotinib, Dasatinib, Erlotinib, Everolimus, Lapatinib, Nilotinib, Pazopanib, Sunitinib, Vandetanib, Venurafenib.

Anti-infection drugs: Erythromycin, Halofantrine, Maraviroc, Primaquine, Quinine, Rilpivirine

Anti-lipemic drugs: Atorvastatin, Lovastatin, Simvastatin

Cardiovascular drugs: Amiodarone, Apixaban, Clopidogrel, Dronedarone, Eplerenone, Felodipine, Nifedipine, Quinidine, Rivaroxaban, Ticagrelor

CNS drugs: Alfentanil (oral), Buspirone, Dextromethorphan, Fentanyl (oral), Ketamine (oral), Lurasidone, Oxycodone, Pimozide, Quetiapine, Triazolam, Ziprasidone

Gastrointestinal drugs: Domperidone

Immunosuppressants: Cyclosporine, Everolimus, Sirolimus, Tacrolimus

Urinary tract drugs: Darifenacin, Fesoterodine, Solifenacin, Silodosin, Tamsulosin

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