The assumption is that what holds true for men can generally be applied to women. Hormonal fluctuations and concerns over pregnancy are often cited as reasons to exclude women from the majority of drug studies. But Arkansas researchers have found that this assumption, when applied to the study of drug interactions, can be erroneous—particularly where grapefruit juice is concerned.

Scott McConnell and Paul Gubbins, pharmacists at the University of Arkansas, studied the effect of grapefruit juice versus water on the metabolism of an oral solution of the antifungal agent itraconazole, in both women and men. Their intent was to determine whether or not grapefruit juice could increase blood serum levels of the poorly absorbed drug. Complicating the problem was the fact that itraconazole is eliminated more rapidly in women than in men.

The enzyme responsible for the drug’s fate is cytochrome P-450 CYP 3A4. For orally administered drugs, the extent of this interaction depends on how much CYP 3A4 is present in the gut. The drug’s faster clearance in women may be linked to either higher levels of or more efficient CYP 3A4 in women.

Furanocoumarins and flavenoids contained in grapefruit juice—6,7-dihydroxybergamottin and quercetin, respectively—denature the enzyme or interfere with it so that drug metabolism is altered, and these compounds are predominantly found in the rind. Thus, concentrated grapefruit juice, which contains the entire fruit, has been fingered as the problem rather than freshly squeezed juice.

In the men, the rate of elimination of itraconazole was similar whether taken with grapefruit juice or water. However, in the women, grapefruit juice caused a dramatic decrease in the rate of elimination from their blood serum. Gubbins warns that people should avoid grapefruit juice altogether while taking calcium channel blockers, which can achieve levels 100–150% higher than normal, resulting in a rapid decline in blood pressure.

The take-home message, says McConnell, is that patients should understand that sex-related differences exist and may play a significant role in the extent of a grapefruit juice–drug interaction. “If you’re taking medication and you want to drink grapefruit juice, you should check with your doctor or pharmacist to make sure there are no safety problems,” advises Gubbins.