CARDIOVASCULAR JOURNAL OF SOUTH AFRICA Vol 18, No.

1, January/February 2007

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The Cardiovascular Prescriber

Grapefruitdrug interactions
Before attempting to provide some insight into grapefruitdrug interactions, it is pertinent to state that there is overwhelming evidence that drug interactions from whatever source and by whatever mechanism do occur, and that many of them have the potential for significant repercussions in terms of enhancing or diminishing various aspects of both the bodys handling of (kinetics), and the expression of medication effects (dynamics) for a wide variety of medications. Grapefruit is one member of a family of citrus fruits, several of which have now been documented as capable of interacting with a variety of medications, and some of these are of particular interest to the cardiovascular prescriber. It seems that Seville oranges, and hence Seville orange marmalade are also destined to be regarded in the same light as grapefruit.1 The components of these citrus varieties that are the source of potential interactions belong to the chemical group known as furanocoumarins. Different varieties of grapefruit and hence also their juice contain varying amounts of these interacting furanocoumarins, and this variability has led to some discrepancies in the data documenting interactions.2 The mechanisms by which these furanocoumarins evoke interactions are centred on the inhibition of one of the prevalent members of the complex family of cytochrome-based enzyme systems known as cytochrome P450-3A4 (CYP3A4), which is very common in the lumen of the gastrointestinal tract (GIT), but is also found in the liver, as well as in various other organs such as the testes, lungs, kidneys and central nervous system. It is the inhibition of this CYP3A4 enzyme system within the lumen of the GIT that is relevant to most of the grapefruit interactions that are of interest and importance to the cardiovascular prescriber. It should be noted that several other foodstuffs and some herbs have been shown to contain furanocoumarins, but in view of the fact that grapefruit and its juice, and possibly also Seville orange marmalade, are such common dietary items, they are more likely to be involved in interactions with important medications. examined the effect of grapefruit juice that had been treated to remove the furanocoumarins, on the kinetics of felodipine in human volunteers. It found that this treated fruit juice did not alter felodipine kinetics and was not different from the effects of ordinary orange juice (which is known to not evoke any significant interactions), but did differ markedly from the effects of furanocoumarin-containing grapefruit juice. This study nicely demonstrates that it is the furanocoumarins that are major interactors.4 Other dihydropyridines that have been reported to interact similarly include some not currently available in South Africa: nitrendipine, nicardipine and nisoldipine. However, a spectrum of available data suggests that it is unlikely that clinically relevant interactions occur with nimodipine, nifedipine and amlodipine.3 There is some support for possible interactions between grapefruit and its juice, and diltiazem and verapamil, which should be taken into consideration. From among the currently available statins, simvastatin, lovastatin and atorvastatin are singled out as having both their kinetic and dynamic profiles notably enhanced by interaction with grapefruit and its juice,5 while pravastatin, fluvastatin and rosuvastatin seem the least likely to interact.6 In view of the potentially serious adverse repercussions from grapefruit interactions with the statins, such as rhabdomyolysis and renal failure, and the elderly may be the most susceptible, careful advice and observation is required. Two other medications that may well belong in the cardiovascular interventionists armamentarium are midazolam7 and diazepam,8 and these too have both their kinetics and dynamics enhanced by concurrent ingestion of grapefruit or its juice. Conversely to the abovementioned interactions where amplification of kinetic and dynamic parameters have been outlined, the beta-blocker acebutolol has been shown to have its kinetic and efficacy parameters somewhat diminished by concurrent intake of grapefruit and its juice.9 The exact mechanisms involved in this interaction are not clear, and indeed the clinical repercussions of the interaction of grapefruit with acebutolol may well be clinically inconsequential. Grapefruit and its juice may enhance drug toxicity for anti-arrhythmic agents such as amiodarone, quinidine, disopyramide and propafenone, and for the alpha 1 betablocker carvedilol.6 Grapefruit interactions with sildenafil, tadalafil, or vardenafil for erectile dysfunction may give rise to serious systemic vasodilatation, especially when combined with a nitrate.6 Fortunately, it seems that interactions between warfarin and grapefruit or its juice are not considered to be of any clinical significance.10 This is indeed a happy finding in view

Some grapefruitdrug interactions of importance to the cardiovascular prescriber

Felodipine, a dihydropyridine calcium channel blocker, has been shown repeatedly to have its absorption increased when administered concurrently with grapefruit or its juice, and that the interaction gave rise to exaggerated effects on blood pressure lowering and heart rate increase.3 This interaction was again observed in another study that

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CARDIOVASCULAR JOURNAL OF SOUTH AFRICA Vol 18, No. 1, January/February 2007

of the large variety of possible drugdrug and fooddrug interactions that are documented to occur with warfarin. (This topic is to be addressed in a future contribution to this Journal.) With the vast array of prescription and over-the-counter medications many of them with low therapeutic indices available to the consumer, but also foodstuffs, herbs, dietary and nutritional supplements, as well as abusive substances such as tobacco and alcohol, the possibility of unwanted interactions should be considered.11 Since altered drug response due to interactions is often widely variable among individuals, the outcome is difficult to predict and avoiding the known interacting combinations will help prevent adverse repercussions. The history taking from every patient should therefore include a careful enquiry into possible sources of drug interactions, and the provision of appropriate advice.
JOHN L STRAUGHAN, BSc (Pharm), MB ChB, BSc (Hons) (Pharm), Dip Clin Pharm (USA), FPS, MFPM (RCP)

References
1. Saito M, Hirata-Koizumi M, Matsumto M, et al. Undesirable effects of citrus juice on the pharmacokinetics of drugs: focus on recent studies.

Drug Saf 2005; 28: 677694. 2. Paine MF, Criss AB, Watkins PB. Two major grapefruit juice components differ in time to onset of intestinal CYP3A4 inhibition. J Pharmacol Exp Ther 2005; 312: 11511160. 3. Sica DA. Interaction of grapefruit Juice and calcium channel blockers. Am J Hypertens 2006; 19: 768773. 4. Paine MF, Widmer WW, Hart HL, et al. A furanocoumarin-free grapefruit juice establishes furanocoumarins as the mediators of the grapefruit juicefelodipine interaction. Am J Clin Nutr 2006; 83: 10972105. 5. Martin J, Krum H. Fooddrug interaction: grapefruit juice augments drug bioavailability: mechanism, extent and relevance. Eur J Clin Nutr 2004; 58, 19. 6. Bailey DG, Dresser GK. Interactions between grapefruit juice and cardiovascular drugs. Am J Cardiovase Drugs 2004; 4: 281297. 7. Goho C. Oral midazolam-grapefruit juice drug interaction. Pediatr Dent 2001; 23: 365366. 8. Ozdemir M, Aktan Y, Boydag BS, et al. Interaction between grapefruit juice and diazepam in humans. Eur J Drug Metab Pharmacokinet 1998; 23: 5559. 9. Lilja JJ, Raaska K, Neuvonen PJ. Effects of grapefruit juice on the pharmacokinetics of acebutolol. Br J Clin Pharmacol 2005; 60: 659663. 10. Sullivan DM, Ford MA, Boyden TW. Grapefruit juice and the response to warfarin. Am J Health Syst Pharm 1998; 53: 15811583. 11. Mertens-Talcott SU, Zadezensky I, De CastroWV , et al. Grapefruit drug interactions: can interactions with drugs be avoided? J Clin Pharmacol 2006; 46: 13901416.