Compounds in grapefruit juice inhibits an enzyme required for metabolism of nearly half of prescription drugs on the market. If you inhibit drug metabolism, would that allow you to take a lower (and cheaper) dose of one of those drugs, especially an expensive drug?
That is the proposition of a company called Bioavailability Systems, featured in today’s Wall Street Journal and alluded to on the WSJ Health Blog (yes, I cite the WSJ very often but only because they have some of the best medical and health reporting on topics well ahead of the MSM curve).
The intestines and the liver contain many drug metabolizing enzymes but the one in question here is a cytochrome P450 monooxygenase called CYP3A4. The enzyme works on drug molecules to slap on a water-soluble chemical group or remove water-insoluble groups. In most (but not all) cases, this action terminates the biological action of the drug.
In 1991, David Bailey and colleagues at the University of Western Ontario reported in The Lancet that grapefruit juice was found to increase blood levels of felodipine, a calcium channel-blocking antihypertensive drug. The precise reason was that grapefruit juice inhibited the CYP3A4 enzyme, an effect that was later ascribed to a group of compounds called furanocoumarins (bergamottin and 6′,7′-dihydroxybergamottin). So, taking felodipine while drinking grapefruit juice was essentially the same as taking a higher dose of the drug because its elimination from the body was slowed. Today’s WSJ article and blog post discuss the experimental and commercial approach to using CYP3A4 inhibitors as “dose boosters” to minimize the dose one needs to take of some very expensive drugs.
My educated prediction is that this approach might not work as well as expected and, worse, could prove to be quite dangerous.
As with herbal medicines, grapefruit juice content of furanocoumarins varies from different suppliers or different lots at different times of the year. So, it is difficult to predict what dose of grapefruit juice to use to increase drug levels to a specific target level. Companies like Bioavailability Systems propose to get around this issue by making a standardized pill that contains known amounts of inhibitor.
Another concern is that large interindividual differences exist in CYP3A4 activity. That is, a dose of grapefruit juice or some inhibitor pill might block half of my CYP3A4 while totally knocking out yours. For a drug like felodipine, this effect might double my blood concentrations but may cause yours to increase 10-fold.
And this is where I am most concerned. Some CYP3A4 substrates have a very narrow window between their therapeutic concentrations and their toxic concentrations. Fiddling with CYP3A4 may lead to unpredictable increases in drug concentrations to a point that mimics getting an overdose of drug.
The rationale given for using grapefruit juice or a commercial inhibitor pill is that it will allow patients to reduce their doses of expensive, oral drugs and save money. Well, I can guarantee that companies like Bioavailability Systems won’t be offering their pill for free, especially since they have isolated unique, patented CYP3A4 inhibitors. And we’ve already discussed that using grapefruit juice is fraught with difficulties in determining the proper dose.
However, I hate to be a naysayer without actually seeing a few well-designed experiments done. Researchers at the University of Chicago are leading a clinical trial to learn if grapefruit juice can be used safely to increase blood levels (and reduce the dose needed) of the expensive immunosuppressive drug, rapamycin.
Of course, I want to be sure this disclaimer and caution is clear to readers, as written in the WSJ:
Don’t Try This at Home
Experts also warn that people should not try boosting on their own to make an expensive medication last longer or make their medicines more effective. Only a clinical trial can show whether the approach is helpful for an individual drug, they say. And it is impossible to know who will respond too strongly or not at all to the grapefruit effect. In people who take multiple drugs, the approach could backfire by interfering with the effects of other medicines that are already working well without boosting.