INTERACTIONS OF GRAPEFRUIT WITH MEDICATIONS

What is present in grapefruit juice which causes these drug interactions?

Dr. David Bailey and Associates at the University of Western Ontario, Canada showed that grapefruit juice acts by blocking (down regulating) the activity (expression) of cytochrome P450 3A4 isoenzyme in the intestinal wall, thereby preventing the presystemic "first-pass" oxidative metabolism (breakdown) for a wide variety of drugs. Grapefruit juice did not significantly block cytochrome P-450 3A4 isozymes in the liver hepatocytes. The net result of blocking this presystemic "first-pass" metabolic pathway, is the potential for a marked increase in the plasma concentration of the drug, often to the point of toxicity. 

For example, in the case of a drug called felodipine (Renedil & Plendil) which they were investigating at the time, there was more than a five fold increase in the plasma concentration with grapefruit juice as compared with water. 

Other studies with the cholesterol lowering drug, lovastatin (Mevacor), showed that grapefruit juice was capable of increasing the peak serum concentration of this drug up to 19.7-fold (range 5.2-19.7) and the area under the concentration-time curve (AUC) up to 26.3-fold (range 5.7-26.3).

The magnitude of the interaction with grapefruit juice appears to be highly variable among individuals, but the effect is relatively consistent for any given person. In addition, there appears to be considerable interracial genetic polymorphism of the cytochrome P450 isozyme subtypes. 

The cytochrome P450 isoenzyme suppression activity of grapefruit juice was found to be accumulative, with an estimated half life at around 12 hours. The suppression effect at the enteric (gut) level, appears to be caused by a degrading (destruction) and not only suppression of the Cytochrome P450 3A4 isozyme. The return of cytochrome P450 3A4 isoenzyme activity appears to require de novo cytochrome P450 isozyme synthesis, further prolonging the effects of grapefruit juice.

Further studies have shown that grapefruit juice will also block other Cytochrome P450 isoenzymes, viz. 1A2 & 3A3. The magnitude of the effects from inhibition of cytochrome P450 1A2 & 3A3 isoenzyme activity by grapefruit juice is relatively minor in comparison to its 3A4 activity, and the clinical significance is relatively unknown. 

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