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Grapefruit-Drug Interaction Seen With More Drugs
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Grapefruit-medication interactions: Forbidden fruit or avoidable consequences?


· Currently, more than 85 drugs have the possibility of interacting with grapefruit; of these drugs, 43 have interactions that can result in serious adverse effects.

· Drugs that interact with grapefruit have all of the following

characteristics: they are administered orally, they have very low to intermediate absolute bioavailability, and they are metabolized by the cytochrome P450 3A4 enzyme (CYP3A4).

· All sources of grapefruit and certain related citrus fruits can irreversibly inhibit CYP3A4 in the gastrointestinal tract; to prevent this interaction, affected drugs should not be consumed with any of these fruits during the treatment period, or noninteracting alternative medications should be prescribed.

· Older patients have the greatest possibility of ingesting grapefruit and interacting medications and are the most vulnerable to the adverse clinical consequences.

CMAJ Nov 26 2012.

David G. Bailey BScPhm PhD, George Dresser MD PhD, J. Malcolm O. Arnold MB BCh MD

"Note that modest amounts of grapefruit intake in all forms appear to trigger interactions with many commonly prescribed classes of drugs", medpagetoday

"all forms of the fruit (freshly squeezed juice, frozen concentrate and whole fruit) have the potential to reduce the activity of CYP3A4. One whole grapefruit or 200 mL of grapefruit juice is sufficient to cause clinically relevant increased systemic drug concentration and subsequent adverse effects.11,12 Seville oranges, (often used in marmalades), limes and pomelos also produce this interaction.13-15 Varieties of sweet orange, such as navel or valencia, do not contain furanocoumarins and do not produce this interaction."

"Affected drugs possess 3 essential characteristics: they have an oral route of administration, they have very low (< 10%) to intermediate (> 30%-70%) intrinsic oral bioavailability, and they are metabolized by CYP3A4."

"The interval between the ingestion of grapefruit and the adminstration of the interacting drug has some effect on pharmacokinetics. For example, a single glass (200 mL) of grapefruit juice ingested within 4 hours before felodipine produced the maximal pharmacokinetic interaction.16 Thereafter, an increased interval between ingesting the 2 substances slowly decreased the size of the effect - an interval of 10 hours produced an effect that was 50% of the maximum, and an interval of 24 hours produced an effect that was 25% of the maximum.16 Thus, a modest solitary quantity of grapefruit can have sufficient duration of action to affect interacting drugs that are administered once daily at any time during the dosing interval. Furthermore, repeated ingestion of grapefruit (200 mL of juice, 3 times/d for 7 d) doubled the size of the interaction for 24 hours, consistent with a cumulative inhibitory action."

"Currently, more than 85 drugs, most of which are available in Canada, are known or predicted to interact with grapefruit. This interaction enhances systemic drug concentration through impaired drug metabolism. Recently, however, a disturbing trend has been seen. Between 2008 and 2012, the number of medications with the potential to interact with grapefruit and cause serious adverse effects (i.e., torsade de pointes, rhabdomyolysis, myelotoxicity, respiratory depression, gastrointestinal bleeding, nephrotoxicity) has increased from 17 to 43, representing an average rate of increase exceeding 6 drugs per year. This increase is a result of the introduction of new chemical entities and formulations....... The actions of drugs are terminated through several biological mechanisms. The most important is drug metabolism involving oxidation by enzymes belonging to the cytochrome P450 superfamily. Cytochrome P450 3A4 is particularly essential, because it is involved in the bioinactivation of about 50% of all drugs.5 CYP3A4 is located in epithelial cells (enterocytes) lining the small intestines and colon, and in the parenchymal cells of the liver (hepatocytes) (Figure 1). Consequently, orally administered drugs can be metabolized twice before reaching the systemic circulation. Thus, the percentage of drug absorbed unchanged (oral bioavailability) can be markedly attenuated. For example, the oral bioavailability of the antihypertensive drug felodipine is normally reduced to 15% of the oral dose.6 In other words, felodipine has low innate bioavailability. For this reason, it is subject to a potentially dramatic increase in systemic exposure and associated higher risk of overdose with grapefruit as a result of diminished CYP3A4 activity, primarily in the small intestine rather than in the liver....... The chemicals in grapefruit involved in this interaction are the furanocoumarins.7 Furanocoumarins are metabolized by CYP3A4 to reactive intermediates that bond covalently to the active site of the enzyme, causing irreversible inactivation (mechanism-based inhibition)...... Grapefruit-interacting drugs can be separated into the 4 categories of very low (< 10%), low (10%-30%), intermediate (> 30%- 70%) and high (> 70%) absolute bioavailability. Drugs with very low bioavailability are the most likely to interact with grapefruit in a way that substantially alters their pharmacokinetics (i.e., analogous to consuming many doses of the drug alone). Conversely, drugs with high bioavailability have a marginally clinically relevant increase in systemic drug concentration....... Indeed, a single usual amount (i.e., 200-250 mL juice or a whole grapefruit) has sufficient potency to cause a pertinent pharmacokinetic interaction.8,11,12 For example, felodipine combined with such a quantity of grapefruit had an average systemic drug concentration that was 3-fold that seen with water.8,11 With twice the amount of grapefruit, there was only a modestly greater increase in the systemic concentration of felodipine, showing that a near-maximal pharmacokinetic interaction had already occurred with the consumption of the single quantity.11 With repeated ingestion of grapefruit (250 mL of juice, 3 times/d for 6 d), a single dose of felodipine increased to 5 times the systemic concentration seen with water, suggesting that frequent consumption of a usual quantity daily augmented the pharmacokinetic effect moreso than the lone quantity. Torsade de pointes and risk of sudden death can occur with excessive prolongation of the corrected QT interval........ Rhabdomyolysis has also been reported with grapefruit ingested at usual amounts (Table 2).21-23 Thus, this adverse outcome with certain statins can occur with the ingestion of much less grapefruit than was previously ex pressed by the US Food and Drug Administration.42 However, taking atorvastatin in the evening and drinking grapefruit juice in the morning (300 mL/d from a specific lot prepared by the Florida Department of Citrus) resulted in drug serum concentrations that were 119%-126% of those seen with no consumption of grapefruit, with no evidence of skeletal muscle toxicity (e.g., elevated creatine phosphokinase, myalgia).43 In addition, pravastatin does not produce a pharmacokinetic interaction with grapefruit,39,40 rosuvastatin is eliminated unchanged,35 and fluvastatin is metabolized by an enzyme (cytochrome P450 2C9) that is not affected by grapefruit.35 Although staggering the ingestion of atorvastatin and grapefruit may reduce risk, substituting pravastatin, rosuvastatin or fluvastatin, or eliminating grapefruit juice from the diet, appears more preferable."

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