PUTTING GRAPEFRUIT INTERACTIONS IN PERSPECTIVE
L. Kendall Shaw, Pharm.D.
Editor/Publisher, RxFactStat.com
Adjunct Associate Professor, College of Pharmacy Lake Erie College of Osteopathic Medicine (LECOM)

      Drug interactions involving grapefruit juice are getting a great deal of attention, as well they should. Like other drug interactions, significant interactions with grapefruit juice can raise a patient’s blood levels of certain medications to substantially raise the potential for toxicity. Of particular concern are interactions with cardioactive medications, which at high blood levels might cause arrhythmia, and some HMGCoA reductase inhibitors (“statins”) with which such interactions can increase the likelihood of myositis or even rhabdomyolysis, muscle disorders that can be painful and even lethal for some. Though these are not by any means the only agents with potentially severe interactions, they are generally the most significant.
 
Novel mechanism of enzymatic interactions     
     Grapefruit juice contains a variety of bioflavonoids noted for binding to and inhibiting or inactivating various cytochrome P450(CYP) isoenzyme systems (primarily CYP1A2, CYP3A3, and CYP3A4) to impair first-pass metabolism of medications that depend on those isoenzymes for metabolism. While clinical significance of such interactions involving hepatic (in the liver) CYP450 enzyme systems are becoming widely-recognized, the inhibiting effects of grapefruit juice bioflavonoids seem almost isolated to the CYP enzyme systems located in the gastrointestinal system, rather than the liver. This is demonstrated by the fact that blood levels of such affected medications remain within normal limits when administered parenterally (by injection). These enzyme systems, located predominantly in duodenal enterocytes (specific cells in the intestine), function normally to reduce the amounts of certain medications that reach circulation. When these enzyme systems are inactivated or inhibited (as if by grapefruit juice), greater amounts of affected orally-administered medications reach the circulation, increasing blood levels and area under the curve – increasing both therapeutic and toxic potentials of affected medications.
     But it isn’t that simple. Recent evidence indicates that components of grapefruit juice also enhance the function of p-glycoprotein efflux pumps, also located in the duodenal enterocytes. This is significant, because p-glycoprotein pumps actively secrete orally-administered and absorbed medications back into the GI lumen (into the intestine), thus reducing their net bioavailability and directly countering the effects of CYP450 isoenzyme inhibition. With both opposing processes occurring simultaneously, it’s difficult to say which will predominate.
     The function of both processes is dictated by genetics, which brings in the science of pharmacogenetics. Just as the function of various CYP450 isoenzyme systems can be predicted to a large extent by patient ethnicity, so can the function of the p-glycoprotein efflux pumps. Since prediction of both opposing processes, though, is only nebulously reliable at this point, it is fair to say that patients will react with great individual variability. To date, there remains no economical or even vaguely reliable way to predict how these two factors might interact in a given patient to anticipate that individual’s ultimate blood levels in response to a given dose of an affected medication in the presence of grapefruit juice.

Conclusion
     The importance of recognizing these interactions is not that grapefruit juice should be avoided when taking medications, even those medications whose blood levels have been proven affected in individual patients. Neither should such medications be avoided in patients whose diets include regular intake of grapefruit juice. The real importance is to simply recognize that such interactions are common; and if the patient normally includes grapefruit juice in his diet and requires an affected medication, it would be prudent to monitor blood levels of affected medications in order to adjust daily dosage accordingly.
     For the patient whose diet usually includes grapefruit juice and discovers he’s been taking a medication on the “affected” list, he should not change either grapefruit juice intake or medication/dosage. Blood levels, again, should probably be monitored; and the clinician should look for anticipated side effects that might indicate toxicity. With similar interactions in mind, (like that between metoprolol and fluphenazine, where fluphenazine typically retards elimination of metoprolol), therapeutic efficacy (and underlying adequate blood level) might actually depend upon regular grapefruit juice intake. Thus, regular grapefruit juice intake is just as likely to enhance therapeutic efficacy as to cause side effects, so long as the possibility of medication toxicity associated with high blood level is obviated.
     In fact, the potential impact of these relatively few interactions might actually warrant inclusion in initial patient questionnaires right along with smoking history and regular alcohol intake. Not that regular consumption of grapefruit juice could remotely be considered a negative health factor like those other two – it’s probably more significant as a positive factor, as a patient attempts to improve his diet and healthy lifestyle. Regular or even sporadic consumption of grapefruit juice should become a factor in the usual prescribing process, simply a factor in choosing the right medication and dose for the individual patient.
     Nor should such interactions be viewed as invariably negative, as contraindications either to consumption of grapefruit juice or medications likely to e affected. They may well be a therapeutic advantage, once their impact on the therapeutic agent is properly assessed. The important point of discussing such interactions is to emphasize that “if it works, don’t fix it.” If proper blood levels of the therapeutic agent are being maintained by current habits of grapefruit juice consumption, neither those habits nor the therapeutic agent or dose should be varied. If blood levels are abnormally high, a decision should be made as to dosage reduction, cessation of grapefruit juice consumption, or a change to another unaffected therapeutic agent.








PUTTING GRAPEFRUIT INTERACTIONS IN PERSPECTIVE L. Kendall Shaw, Pharm.D. Editor/Publisher, RxFactStat.com Adjunct Associate Professor, College of Pharmacy Lake Erie College of Osteopathic Medicine (LECOM)
Drug interactions involving grapefruit juice are getting a great deal of attention, as well they should. Like other drug interactions, significant interactions with grapefruit juice can raise a patient’s blood levels of certain medications to substantially raise the potential for toxicity. Of particular concern are interactions with cardioactive medications, which at high blood levels might cause arrhythmia, and some HMGCoA reductase inhibitors (“statins”) with which such interactions can increase the likelihood of myositis or even rhabdomyolysis, muscle disorders that can be painful and even lethal for some. Though these are not by any means the only agents with potentially severe interactions, they are generally the most significant
Acidity could pose problems
Novel mechanism of enzymatic interactions Grapefruit juice contains a variety of bioflavonoids noted for binding to and inhibiting or inactivating various cytochrome P450(CYP) isoenzyme systems (primarily CYP1A2, CYP3A3, and CYP3A4) to impair first-pass metabolism of medications that depend on those isoenzymes for metabolism. While clinical significance of such interactions involving hepatic (in the liver) CYP450 enzyme systems are becoming widely-recognized, the inhibiting effects of grapefruit juice bioflavonoids seem almost isolated to the CYP enzyme systems located in the gastrointestinal system, rather than the liver. This is demonstrated by the fact that blood levels of such affected medications remain within normal limits when administered parenterally (by injection). These enzyme systems, located predominantly in duodenal enterocytes (specific cells in the intestine), function normally to reduce the amounts of certain medications that reach circulation. When these enzyme systems are inactivated or inhibited (as if by grapefruit juice), greater amounts of affected orally-administered medications reach the circulation, increasing blood levels and area under the curve – increasing both therapeutic and toxic potentials of affected medications. But it isn’t that simple. Recent evidence indicates that components of grapefruit juice also enhance the function of p-glycoprotein efflux pumps, also located in the duodenal enterocytes. This is significant, because p-glycoprotein pumps actively secrete orally-administered and absorbed medications back into the GI lumen (into the intestine), thus reducing their net bioavailability and directly countering the effects of CYP450 isoenzyme inhibition. With both opposing processes occurring simultaneously, it’s difficult to say which will predominate. The function of both processes is dictated by genetics, which brings in the science of pharmacogenetics. Just as the function of various CYP450 isoenzyme systems can be predicted to a large extent by patient ethnicity, so can the function of the p-glycoprotein efflux pumps. Since prediction of both opposing processes, though, is only nebulously reliable at this point, it is fair to say that patients will react with great individual variability. To date, there remains no economical or even vaguely reliable way to predict how these two factors might interact in a given patient to anticipate that individual’s ultimate blood levels in response to a given dose of an affected medication in the presence of grapefruit juice.

Conclusion
     The importance of recognizing these interactions is not that grapefruit juice should be avoided when taking medications, even those medications whose blood levels have been proven affected in individual patients. Neither should such medications be avoided in patients whose diets include regular intake of grapefruit juice. The real importance is to simply recognize that such interactions are common; and if the patient normally includes grapefruit juice in his diet and requires an affected medication, it would be prudent to monitor blood levels of affected medications in order to adjust daily dosage accordingly.
     For the patient whose diet usually includes grapefruit juice and discovers he’s been taking a medication on the “affected” list, he should not change either grapefruit juice intake or medication/dosage. Blood levels, again, should probably be monitored; and the clinician should look for anticipated side effects that might indicate toxicity. With similar interactions in mind, (like that between metoprolol and fluphenazine, where fluphenazine typically retards elimination of metoprolol), therapeutic efficacy (and underlying adequate blood level) might actually depend upon regular grapefruit juice intake. Thus, regular grapefruit juice intake is just as likely to enhance therapeutic efficacy as to cause side effects, so long as the possibility of medication toxicity associated with high blood level is obviated.
     In fact, the potential impact of these relatively few interactions might actually warrant inclusion in initial patient questionnaires right along with smoking history and regular alcohol intake. Not that regular consumption of grapefruit juice could remotely be considered a negative health factor like those other two – it’s probably more significant as a positive factor, as a patient attempts to improve his diet and healthy lifestyle. Regular or even sporadic consumption of grapefruit juice should become a factor in the usual prescribing process, simply a factor in choosing the right medication and dose for the individual patient.
     Nor should such interactions be viewed as invariably negative, as contraindications either to consumption of grapefruit juice or medications likely to e affected. They may well be a therapeutic advantage, once their impact on the therapeutic agent is properly assessed.
     The important point of discussing such interactions is to emphasize that “if it works, don’t fix it.” If proper blood levels of the therapeutic agent are being maintained by current habits of grapefruit juice consumption, neither those habits nor the therapeutic agent or dose should be varied. If blood levels are abnormally high, a decision should be made as to dosage reduction, cessation of grapefruit juice consumption, or a change to another unaffected therapeutic agent.