INTERACTIONS OF GRAPEFRUIT WITH MEDICATIONS

How Does Grapefruit Cause Such Interaction with Medications?

Grapefruit juice affects the bioavailability (therapeutic concentration) of a very wide variety of drugs. All drugs, to greatly differing degrees, achieve their respective target therapeutic levels by two main regulatory pathways, both involving one or more of the 30+ related cytochrome P450 isozymes.

The initial elimination route, called the presystemic "first-pass" metabolic pathway, involves the the gut (small intestine), the portal vein and the the liver. Depending on the drug or food supplement in question, this critical "first-pass" metabolic degradation will directly determine both the peak and mean concentrations of the drug or its metabolite in the blood stream.

Some drugs, such as terfenadine (Seldane) requires 100% breakdown by this presystemic "first-pass" metabolic pathway to convert it to its active and less toxic metabolite, terfenadine carboxylate. Any drug, (such as erythromycin, ketoconazole (Nizoral)) or food such as grapefruit juice, that inhibits or competes for the enteric (gut) cytochrome P-450 3A4 isozyme, will partially or completely block this metabolic step (breakdown) of terfenadine, and will result in the absorption of unmetabolized terfenadine, with the potential for very serious toxic reactions including ventricular tachyarrithmias (cardiac arrest) and death. 

Approximately one hundred and twenty five deaths have now been linked to the concomitant use of terfenadine and one of the previously listed products that interferes with the Cytochrome P450 isoenzyme. Other drugs, e.g. prednisone, quinidine, theophylline, etc. with a high oral bioavailibility, or not competing for the same cytochrome P-450 3A4 isozyme, will not be affected by ingestion with grapefruit juice.

The second elimination pathway for all drugs involves the more predictable metabolic degradation over time by the hepatocytes in the liver, and excretion in the bile or by the kidneys. Grapefruit juice will not have any effect on the drugs that uses this second elimination pathway. It only affect the "first-pass" small intestine - liver metabolic pathway and not any secondary elimination metabolic processes. That is why some drugs are affected by grapefruit juice while others are not.

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