In FASS (the Swedish catalogue of approved medical products) it is mentioned that grapefruit juice

Fråga: In FASS (the Swedish catalogue of approved medical products) it is mentioned that grapefruit juice has a potential to cause pharmacological interactions with various drugs (1). Does this also apply to the whole fruit, and not only the extracted juice? Could other grapefruit-like citrus fruits such as pomelo cause similar interactions?

Sammanfattning: There is some evidence that the association between grapefruit juice and elevated plasma levels of various drugs can be extended to the whole, unprocessed fruit. Some other citrus fruits, e.g. pomelo, Seville orange and lime, could possibly cause similar pharmacokinetic interactions.

Svar: Grapefruit juice has a potential to interact pharmacologically with a number of drugs, e.g. calcium channel blockers, statins, and immunosuppressants. The mechanism involves inhibition of drug metabolising cytochrome P450 (CYP) enzymes, CYP3A4 in particular, and drug transporters such as P-glycoprotein. It has been suggested that the inhibiting effect of grapefruit juice is caused by furanocoumarins such as bergamottin, but psoralens could also contribute to its inhibitory potential (2).

Although most studies on grapefruit interactions have used extracted grapefruit juice in amounts from 200 mL and upwards, decreased tacrolimus dose requirements have been observed after exposure to 100 mL grapefruit juice - less than the juice content of one fruit (3, 5). However, commercial grapefruit juice usually contains small amounts of peel and other non-segmental parts of the grapefruit, and it has been suggested that consumption of fruit segments or freshly squeezed juice may be less prone to cause interactions. This notion is contradicted by a study demonstrating that both commercial juice, fruit segments, and extract of the non-segmental parts caused felodipine interactions of similar magnitude in vivo and inhibited CYP3A4 in vitro (4). Furthermore, ingestion of one whole grapefruit per day has been associated with carbamazepine toxicity (5).

In addition to grapefruit, both Seville orange (Citrus aurantium) and pomelo (Citrus grandis) have been associated with clinically relevant pharmacokinetic interactions similar to those ascribed to grapefruit juice (5, 6). Other citruses with high furanocoumarin content include lime (Citrus aurantifolia) and hassaku (Citrus hassaku), both of which inhibit CYP3A4 in vitro. Interestingly, the sweet citruses satsuma (Citrus unshu) and dekopon (Citrus reticulata), both devoid of furanocoumarins, increase CYP3A4 activity in vitro. The clinical implications of this finding are, however, unknown (7, 8). http://www.fass.se/LIF/produktfakta/fakta_lakare_artikel.jsp?articleID=18352 Eriksson M. Clinically significant interactions between grapefruit juice and drugs. Exam Project for a Master of Science in Pharmacy. Department of Pharmaceutical Biosciences: Uppsala University; 2006. http://www.dole5aday.com/ReferenceCenter/Encyclopedia/Grapefruit/index.jsp?topmenu=1 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(5):468-477 Baxter K (Ed), Stockley´s Drug interactions. London: Pharmaceutical Press. Electronic version (2006-10-06) Malhotra S, Bailey DG, Paine MF, Watkins PB. Seville orange juice-felodipine interaction: comparison with dilute grapefruit juice and involvement of furocoumarins. Clin Pharmacol Ther 2001;69(1):14-23 Saita T, Fujito H, Mori M. Screening of furanocoumarin derivatives in citrus fruits by enzyme-linked immunosorbent assay. Biol Pharm Bull 2004;27(7):974-977 Fujita K, Hidaka M, Takamura N, Yamasaki K, Iwakiri T, Okumura M et al. Inhibitory effects of citrus fruits on cytochrome P450 3A (CYP3A) activity in humans. Biol Pharm Bull 2003;26(9):1371-1373