The power in grapefruit. .

What can we say about grapefruit (citrus paradisi), the large cousin of the ubiquitous orange? An amount of 100 gm of grapefruit contains (1) 6.8 g total sugars, (glucose, fructose and sucrose), 1.6 g fibre, 0.8 g protein, 89% water, negligible fat and sodium. Its only important inorganic nutrient is potassium; its only useful amounts of vitamins are 36 mg vitamin C and 26 [micro]g folate (and if it has pink flesh this is coloured by carotenoids). Grapefruit contains less sugar than oranges (1) and more citric and malic acids (2). This food table information does not really explain why fruits-taking grapefruit as an example- appear to be specially good for our health. There must be other bioactive substances (3,4), some only known to a few specialist chemists. One of the major areas of nutrition research today is to find out more about potentially bioactive substances, other than vitamins and minerals in our food.

Nothing gives a better idea of the power of these largely unknown substances, taken for granted, in fruits than the grapefruit-drug interactions. Bailey and Spence and colleagues at the University of Western Ontario (5) made the serendipitous discovery that grapefruit juice interferes with the metabolism of felodipine, a calcium channel blocking anti-hypertensive. They had been using grapefruit juice concentrate to mask the flavour of ethanol, which they were testing for possible interaction with this particular drug (5).

When a glass of grapefruit juice was taken at about the same time as the felodipine, the area under the curve of plasma drug level and the peak concentration increased more than twofold. The blood pressure lowering was greater and so were side effects (headaches, facial flushing, lightheadedness). Orange juice by contrast did not have these effects.

It has been since found that the bioavailability of a considerable list of modem drugs (Table 1) is enhanced by a standard glass of grapefruit juice (6). The drugs belong to several different pharmacological families, including calcium channel blockers used for hypertension, some of (not all) the statins used to lower blood cholesterol, cyclosporin and tacrolimus used to reduce transplant graft rejection, anti-HIV agent saquinavir, the anti-convulsant carbamazepine ('tegretol'), short-acting benzodiazepine sedatives midazolam and triazolan, as well as the different drugs cisapride and buspirone.

The interaction is most important for drugs with potentially severe side effects. With calcium blockers (like felodipine) grapefruit juice increases the chance of flushing, ankle oedema and faintness. With statins sensitive to the interaction there is the possibility of myotoxicity. With cyclosporin plasma concentrations have to be kept within a narrow range to achieve immunosuppression without nephrotoxicity. With cisapride there is a danger of ventricular arrhythmias. This type of dangerous arrhythmia occurred in an interaction of grapefruit juice with the non-sedative antihistamine terfenadine which has now been withdrawn. The entries on susceptible drugs in MIMS and MIMS annual (MediMedia Australia Pty Ltd) usually mention grapefruit juice in the small print on interactions but this is not completely reliable. On simvastatin and on saquinavir, for example, one proprietary product includes grapefruit among the interactions but another one does not.

The New South Wales Health Department issued a warning notice about taking certain drugs with grapefruit or grapefruit juice in August 2002 (7). 'Grapefruit and its juice increase the availability of certain drugs within the body that can lead to increased side effects.' These are some drugs 'prescribed for high blood pressure, organ transplantation, to lower blood cholesterol, for HIV/AIDS or for epilepsy.. .Different people react differently but some of the possible side effects include heart rhythm disturbances, kidney function impairment, blood pressure changes and anaemia' (7). NSW health authorities decided to issue the alert to follow the lead of their Canadian counterparts. There was no need to avoid other sources of vitamin C like oranges (8).

When grapefruit juice is taken with a susceptible drug, the peak plasma drug concentration (C max) is increased but the descending limb of the curve is at the same angle-the elimination half life is at the usual rate. Grapefruit has no effect on the pharmacokinetics of an intravenously administered drug, felodipine (10) which has been used as a model to investigate the grapefruit interaction. The effect of grapefruit is on first, or pre-systemic metabolism of the drug in the wall of the small intestine (6) by cytochrome P450 3A4 (CYP3A4), one of the cytochrome P450 superfamily of enzymes (11). After administration of grapefruit, small intestinal biopsy shows reduced CPY3A4 protein (12), but its mRNA was not changed, so the enzyme inhibition is post-transcriptional.

There is considerable variability in the grapefruit interaction, both between drugs and between individuals (though within individuals it is reproducible). It appears that the greater the usual pre-systemic metabolism and enterocyte content of CYP3A4, the more bioavailability is likely to increase after grapefruit. The interaction of grapefruit with these drugs metabolised by intestinal CYP3A4 is similar to a drug-drug interaction with erythromycin, which suppresses CYP3A4. Not all drugs in a pharmacological group have their bioavailability affected by grapefruit. A notable exception is pravastatin, the HMG Co A reductase inhibitor, which is not metabolised by CYP450 (13) and is not affected by grapefruit ingestion (14).

It has been difficult to establish which is or are the responsible substance(s) in grapefruit. They must be substances not present (or in much smaller amounts) in oranges. There could be different substances in the fruit segments, in the commercially processed juice and in the peel, The early research on drug interactions was done with commercial processed grapefruit juice but it has been demonstrated that grapefruit segments also cause an interaction with felodipine (15). An early candidate was naringin, a glycoside of the flavonone naringenin with the disaccharide rhamnoglucose. It has a bitter flavour and is present in grapefruit and Seville oranges. However, pure naringin, corresponding to the amount of grapefruit juice had only a small effect on felodipine plasma concentration. This could be only partly explained by different proportions of the two optical isomers of naringin. Grapefruit, and not orange juice, also contains several furanocoumarins, such as 6',7'dihydrobergamottin. This has not been avai lable pure for human administration. Bailey et al. therefore separated grapefruit juice into fractions that contained different amounts of naringin and 6'7'dihydrobergamottin. A particulate fraction, lower in these two substances, was more active than the supernatant fraction that contained more of them (16). There must therefore be at least one other active substance in grapefruit. A possibility is bergamottin, which is a potent inhibitor of CYP3A4 in vitro and was concentrated in the particulate fraction in the experiments of Bailey et al. (16). There are several compounds and dimers of bergamottin in grapefruit juice and in vitro they have inhibitory effects on CPY3A4 (17).

Up to now the developing story of how grapefruit and its juice (and probably peel) increases drug bioavailability has appeared only in the specialist pharmacological literature. But dietitians often see patients taking one (or more) of the drugs in Table 1 and are likely to encourage fruit consumption as part of their background advice. They should therefore be aware of this interaction. JD Spence, one of the discoverers of the interaction asks whose responsibility is it to warn the public (1). He even suggests warnings on the grocery counters where grapefruit and grapefruit juice are sold (the need for this may be less urgent since terfenadine has been withdrawn). Meanwhile for the majority of people not taking those drugs in the table, we can contemplate, as we drink our delicious grapefruit juice, that there's more in this fruit than the food tables tell you.

A. Stewart Truswell

Emeritus Professor of Human Nutrition

The University of Sydney 

Table 1

Drugs whose metabolism is inhibited and bioavailability increased
by grapefruit juice (6,7)

Anti-hypertensive Calcium channel blockers
      FELODPINE ('Agon'; 'felodur'; 'Plendil'
      NIFEDIPINE ('Adalat'; 'Nyefax')
      NISOLDIPINE
      NITRENDIPINE
      NIMODIPINE ('Nimotop')

Certain HMG CoA Reductase inhibitors
      SIMVASTATIN ('Lipex'; 'Zocor')
      LOVASTATIN
      ATORVASTATIN ('Lipitor')

Immunomodifiers
      CYCLOSPORIN ('Neoral')
      TACROLIMUS ('Prograf')

An Anti-convulsant
      CARBAMAZEPINE ('Tegretol')

Certain Benzodiazepine sedatives
      MIDAZOLAM ('Hypnovel')
      TRIAZOLAM ('Halcion')

Certain Anti-viral agents
      INDINAVIR ('Crixivan')
      SAQUINAVIR ('Invirase'; 'Fortovase')

GI Motility stimulant
      CISAPRIDE ('Prepulsid')

An Azopirone Anxiolytic
      BUSPIRONE ('Buspar') (9)

References

(1.) Holland B, Unwin ID, Buss DH. Fruit and Nuts. The first supplement to McCance and Widdowson's The Composition of Food (5th ed). Cambridge Royal Society of Chemistry; 1992.

(2.) Coultate TP. Food, the chemistry of its components. London: Royal Society of Chemistry; 1984.

(3.) Truswell AS. Protective plant foods: new opportunities for health and nutrition. Food Australia 1997;49:40-53.

(4.) Leitzmann C. Other biological active substances in plant foods. In: Mann J and Truswell AS, editors. Essentials of human nutrition 2nd ed. Oxford: Oxford University Press; 2002. p.259-69.

(5.) Bailey DG, Spence JD, Munoz, C, Arnold JMO. Interaction of citrus juices with felodipine and nifedipine. Lancet 1991;337:268-9.

(6.) Bailey DG, Malcolm J, Arnold O, Spence JD. Grapefruit juice-drug interactions. Br J Pharmacol 1998;46:101-10.

(7.) NSW Chief Health Officer public alert. Grapefruit juice alert. www.health.nsw.gov.au August 2002.

(8.) Alert links grapefruit to drug risk. Sydney Morning Herald 2002 August 15:7.

(9.) Lilja JJ, Kivisto KT, Backmann JT, Lamberg TS, Neuvonen PJ. Grapefruit juice substantially increases plasma concentrations of buspirone. Clin Pharmacol Ther 1998;64:655-60.

(10.) Lundahl J, Regardh CG, Edgar B, Johnsson G. Effect of grapefruit juice ingestion--pharmacokinetics and haemodynamics of intravenously administered felodipine in healthy men. Eur J Clin Pharmacol 1996;52:139-45.

(11.) Nebert DW, Russell DW. Clinical importance of the cytochromes p450. Lancet 2002;360:1155-62

(12.) Lown KS, Bailey DG. Fontana RJ, Janardan SK, Adair CH, Fortlage LA et al. Grapefruit juice increases felodipine oral availability in humans by decreasing CYP3A4 protein expression. 3 Clin Invest 1997;99:2545-53.

(13.) Farmer JA. Learning from the cerivastatin experience. Lancet 2001;358:1383-4.

(14.) Lilja JJ, Kivisto JT, Neuvonen PJ. Grapefruit juice increases serum concentration of atorvastatin and has no effect on pravastatin. Clin Pharmacol Ther 1999;66:118-27.

(15.) Bailey DG, Dresser GK, Kreeft JH, Munoz C, Freeman DJ, Bend JR. Grapefruit-felodipine interaction: effect of unprocessed fruit and probable active ingredients. Clin Pharmacol Ther 2000;68:468-77.

(16.) Bailey DG, Kreeft JH, Munoz C, Freeman DK, Bend JR. Grapefruit juice-felodipine interaction: effect of naringin and 6'7' dihydroxybergamottin in humans. Clin Pharmacol Ther 1998;64:248-56.

(17.) Guo L-Q, Fukuda K, Ohta T, Yamozoe Y. Role of furanocoumarin derivatives on grapefruit-mediated inhibition of human CYP3A4 activity. Drug Metabol Dispos 2000;28:766-71.

(18.) Spence JD. Drug interactions with grapefruit: whose responsibility is it to warn the public? Clin Pharmacol Ther 1997;61:395-400.