Is there a risk for interaction between grapefruit and metoprolol, candesartan, hydrochlorothiazide

Fråga: Is there a risk for interaction between grapefruit and metoprolol, candesartan, hydrochlorothiazide and amlodipine respectively? The question concerns a patient taking metoprolol and candesartan/hydrochlorothiazide (Atacand Plus) and that may be prescribed amlodipine (Norvasc). The patient is very fond of grapefruit, which is the reason for the consultation.

Sammanfattning: There is not any clinical evidence or pharmacologic reason to suspect an interaction between grapefruit juice and metoprolol, candesartan or hydrochlorothiazide respectively. Grapefruit juice interacts with several calcium-blockers even though the clinical effect regarding most generics seems to be small. There is no evidence in clinical trials of a clinical significant interaction between grapefruit juice and amlodipine even though its bioavailability may be affected. However, on an individual basis an interaction may be possible why the intake of grapefruit juice of a patient medicating with amlodipine should be followed by caution and attention for adverse effects such as symptoms of low blood pressure.

Svar: The mechanism for the interaction between grapefruit juice and drugs is uncertain even though inhibition of the activity of CYP3A4 in the intestinal wall increasing the bioavailability of the drug has been suggested. Metoprolol is a beta-blocker metabolised in the liver mainly by CYP2D6 (1). Candesartan has an antagonistic effect on angiotensin II receptors. To the greatest extent it is eliminated unaltered, but a smaller proportion is being substrate for CYP2D6 in the liver. Hydrochlorothiazide is not metabolised (2). Amlodipine acts by blocking the calcium channels in the heart and smooth muscles around the body and thereby dilates peripheral arterioles and coronary arteries. CYP3A4 is important for the metabolisation of amlodipine (3).

No evidence of interactions between grapefruit juice and metoprolol, candesartan, and hydrochlorothiazide respectively was found searching Medline.

Grapefruit juice interacts with drugs metabolised by CYP3A4, such as calcium-blockers and the makers of felodipine as well as those of lercanidipine, nifedipine, nimodipine, nisoldipine and verapamil in fact contraindicate concurrent intake of grapefruit juice. The clinical relevance is however regarded as small, and generally speaking concomitant use of grapefruit juice and most calcium channel blockers other than felodipine and possibly nisoldipine, need not to be avoided (4). Regarding amlodipine. One study show that the bioavailability of amlodipine may be slightly increased by the intake of grapefruit juice (5) even though no effect on neither heart rate nor blood pressure was shown. Another study did not show any differences in neither bioavailability nor clinical features following administration of grapefruit juice (6).

The mechanism for the interaction between grapefruit juice and calcium-blockers is uncertain even though inhibition of the activity of CYP3A4 in the intestinal wall by flavonoids or possibly furanocoumarins increasing the bioavailability of the calcium-blocker has been suggested. This may explain why most calcium-blockers with a low oral bioavailability are most affected by concurrent intake of grapefruit juice such as felodipine, while for example amlodipine and diltiazem with high bioavailability are the least affected. Another suggested mechanism involves the inhibition of furanocoumarines of the intestinal P-glucoprotein efflux transport (4).