Last modified: 11 May 2000
Blood levels of cyclosporine are increased if taken with grapefruit juice. Cyclosporine is metabolized by an enzyme called P450 3A4 which is primarily found in the small intestine and the liver. The effect of grapefruit juice on cyclosporine blood levels (and on the blood levels of some other medications which are also metabolized by this enzyme) has been theorized to result from an inhibition of intestinal P450 3A4 by a group of molecules called flavinoids which are found in grapefruit juice. While it appears to be true that grapefruit juice will increase cyclosporine blood levels, the exact role of flavinoids and the exact mechanism by which grapefruit juice causes these increases is not proven with certainty.
The problems lie in the fact that there are no standard doses of grapefruit juice. Each fresh grapefruit, each brand of juice, and different cans of the same brand of grapefruit juice may deliver a different dose of "grapefruit juice activity", and thereby effect cyclosporin absorption and metabolism differently. In addition, the few studies which ahve been carried out to date have largely been performed in normal volunteers and have been of short duration. These studies may not be applicable to all classes of transplant patients or to long term usage.
At the University of Michigan, we do not recommend the use of grapefruit juice to reduce the dose and, thus, the cost to the patient of cyclosporine. We believe that there exist safer strategies to address this issue including changing patients from once daily to twice daily dosing which often reduces the total daily dose required, instituting the Neoral&tm cyclosporine preparation which will be commercially available in the fall, reviewing insurance coverage and sometimes obtaining Medicaid or changing insurance carriers, and applying to NORD (National Organization for Rare Diseases) for assistance.
It is very important to keep cyclosporine levels in therapeutic ranges to protect transplants from undertreatment and the risk of developing rejection, and from overtreatment and the risks of cyclosporin toxicity, infection and the development of cancer. We strongly recommend that transplant patients NOT try to adjust their cyclosporine doses on their own, but that they discuss with their transplant center any problems which they may have in paying for their medications and work with their transplant center to find a safe solution.
Alan Leichtman, MD
Transplant Nephrologist, University of Michigan Medical Center
Last modified:
11 May 2000