An understanding of the potential for pharmacokinetic interaction between orally administered drugs and grapefruit is necessary in view of an increase in marketed medications that fit the risk criteria, suggest Canadian researchers.
Currently, more than 85 drugs have the potential to interact with grapefruit, with the number that could induce serious adverse effects - including torsade de pointes, rhabdomyolysis, myelotoxicity, respiratory depression, and gastrointestinal bleeding - rising from 17 to 43 between 2008 and 2012.
This "disturbing trend" is a "result of the introduction of new chemical entities and formulations," write David Bailey (Lawson Health Research Institute, London, Ontario) and colleagues in a review published in the Canadian Medical Association Journal.
The most well-known and studied interaction between grapefruit, other citrus fruits such as Seville oranges, limes, and pomelos, and certain drugs is the interference in activity of the cytochrome P450 3A4 enzyme (CYP3A4).
CYP3A4 is essential for the bioinactivation of about 50% of all drugs. However; the furanocoumarins found in grapefruit are metabolized by this enzyme, causing irreversible inactivation.
Indeed, just one grapefruit, or 200 mL of grapefruit juice is sufficient to cause a clinically relevant increased systemic drug concentration, remark Bailey et al. They use the example of the antihypertensive drug felodipine, circulating levels of which become three times higher when used with grapefruit than with water.
Previous research also shows that patients with elevated levels of CYP3A4 in the small intestine before ingesting grapefruit appeared to be at increased risk for drug interactions, giving a possible means of identifying those at greater risk before exposure to an interacting combination.
However, it is "impractical" to routinely determine enterocyte CYP3A4 content in clinical practice, say the researchers.
Patients aged over 70 years may be at higher risk for a more pronounced pharmacokinetic interaction as a result of this population's propensity to buy grapefruit and receive prescriptions. Furthermore, older adults can have a decreased capacity to compensate for excessive systemic drug concentrations.
"For example, felodipine (which normally lowers blood pressure) does not cause a compensating increase in heart rate in older adults when ingested with grapefruit, but does in young and middle-aged people," the authors explain.
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