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Careful with Grapefruit: Enhances Some Drugs, Blocks Others, Impacts Vinblastine

citrus Photo by isatoriApril 7, 1999. Grapefruit have been valued as part of an anti-prostate cancer diet along with tomatoes and strawberries. Red-fleshed grapefruit contains lycopene, an antioxidant that appears to help prevent prostate cancer. And citrus fruit compounds, as reported below, may have immune-boosting and anti-cancer effects.

     But substances in grapefruit have quite powerful effects on the body's absorption of many widely-prescribed medications. New evidence suggests that consuming grapefruit juice could interfere with a chemotherapy drug used for prostate cancer, Vinblastine.

From Blood Pressure Drugs to Chemo

     Drinking a glass of grapefruit juice when taking certain medications has long been known to help the body absorb the drug. This "grapefruit effect" is distinct from the need for acidity to dissolve some tablets such a Nizoral (ketoconazole). If you've been advised to drink orange juice along with Nizoral, you should of course continue to follow your doctor's instructions.

     A couple of years ago, studies showed that grapefruit improves absorption of drugs including calcium channel blockers and HIV-protease inhibitors. Now comes another twist. Grapefruits vary according to how and where they're grown. The state of people's innards varies. More than one set of intestinal chemicals is involved. And depending on the drug, the "grapefruit effect" could either boost it or block it.

     The latest study has found that grapefruit blocks absorption of some drugs. One of the drugs blocked, Vinblastine, is used in chemotherapy for prostate cancer. Scientists at the University of California at San Francisco (UCSF) reported last week that laboratory tests on cells show that grapefruit juice may have a negative impact on the body's absorption of many widely-prescribed medications including Vinblastine.

Bombers in a Glass of Juice, Potent Metabolic Effects

      The grapefruit effect was discovered by happy chance almost a decade ago when scientists gave volunteers grapefruit juice to mask the taste of a medication. A single glass can significantly increase the absorption of a number of commonly used oral medications including nearly all calcium channel blockers (used to control blood pressure), some sedatives, and some immunosuppressants and protease inhibitors (used for transplants and to treat AIDS).

      How the grapefruit effect works was unknown until Dr. Paul Watkins and colleagues at the University of Michigan Medical Center in Ann Arbor reported in May 15 1997 Journal of Clinical Investigation that grapefruit juice decreases the amount of an enzyme, called CYP3A4, already known to be present in the small intestine.

     This narrowed the search for substances in grapefruit juice that affect drug metabolism. Pinpointing these could enable manufacturers to produce safer and more effective medications.

     Dr. Watkins went on to isolate a pair of substances in grapefruit that do this. In the November 1997 issue of Drug Metabolism and Disposition, he and his UM colleagues reported that these two components act like suicide bombers, attaching themselves to the CYP3A4 and stopping it from interfering with drug absorption.

     After taking grapefruit juice, everyone in the study had virtually the same level of CYP3A4. Normally, indivuals vary in how much CYP3A4 their intestines churn out. This normal variation, by affecting metabolism of drugs, impacts drug safety. A dose that is right for one individual can be ineffective or even toxic to another. The researchers were excited to realize that adding the active substance in grapefruit to a medication could produce a drug for which a standard dosage would be equally effective in everyone.

     But not only are people's guts variable -- so are grapefruits. The concentration of the active ingredients varies dramatically among grapefruits and grapefruit juices, even within the same product line. This is most likely, the researchers say, because of growing conditions in different regions and because manufacturers typically buy their grapefruits from many areas. "For this reason," Watkins said in November 1997, "it would be preferable to add the active ingredient to pills, rather than just taking medication with grapefruit products."

     Asked what people who regularly take drugs that are metabolized by CYP3A4 should do about grapefruit in their diet, Dr. Lown said, "Consistency is the key." "If you regularly drink grapefruit juice, don't change. If you are on these drugs and don't normally take them with grapefruit juice, you may need to consult your physician before adding grapefruit juice to your diet."

New Caution Over Blocking Interaction

     In the latest study, published in the April 1999 issue of Pharmaceutical Research, Dr. Andrea Soldner and other scientists at UCSF show that grapefruit juice can actually inhibit the body's absorption of certain drugs including:

  • Vinblastine (for combating cancer)
  • Cyclosporine (for supressing organ rejection following transplant)
  • Losartan (for controlling high blood pressure)
  • Digoxin (for treating congestive heart failure)
  • Fexofenadine (for alleviating allergy symptoms)
This blocking of drug activity occurs because an unknown substance in grapefruit juice activates a naturally-produced chemical, P-glycoprotein, in the intestinal tract. When grapefruit juice interacts with P-glycoprotein, the result is an increased likelihood that certain drugs will be stopped from entering the bloodstream.

     "These findings help to clarify some major discrepancies we've noticed in the impact of grapefruit juice on various types of medications," said Dr. Leslie Benet, professor of Biopharmaceutical Sciences at UCSF and director of the study. Patients already taking grapefruit juice with their medications can continue to do so, he said. But patients on drugs identified as specifically affected by this blocking effect, " may get a further increase in absorption by taking their drugs a couple of hours after a glass of grapefruit juice."

     According to Dr. Benet, patients who have not previously taken their drugs with grapefruit juice "should be very cautious in doing so, since we now recognize, depending on the drug, that grapefruit juice may either increase or decrease levels of drug in the blood, leading to potential concerns for toxicity or lack of efficacy."

Dr. Paul Watkins's research was supported by NIH-National Institute of General Medical Sciences and University of Michigan Medical Center

Dr. Leslie Benet at UCSF is founder of American Association of Pharmaceutical Scientists

Citrus Limonoids May Have Anti-Cancer Effects

Posted April 7, 1999. Limonoids, found in the skin of citrus fruits, could have significant health benefits, scientists said last month at the American Chemical Society conference. Limonoids may have anti-cancer effects.

     Limonoids are compounds found in citrus fruits, usually in the peels. They produce the bitter taste and zesty aroma. Citrus limonoids are present in commercial orange juice at about the same level as vitamin C.

     Some researchers think citrus limonoids may be responsible for health effects previously attributed to vitamin C. A Japanese company, Wakayama Prefectual Federation of Agricultural Co-operatives, is making an orange juice with triple the level of limonoid glucosides.

     Preliminary research found limonoids could prevent and halt cancer under laboratory conditions. They had anti-cancer effects in animals and prevented the spread of human breast cancer in a cell culture. Scientists are now exploring their use more fully.

     The effect in the human body and on other types of cancer has not yet been tested. So far the work has progressed from cells to mice, the researchers reported at the conference. Another team is testing the performance of 12 limonoids in preventing cancer in humans.

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