Background
That grapefruit juice can cause drug-drug interactions was discovered by chance in a clinical trial in 1989 and confirmed in an experiment by the same research group in 1991 (Bailey et al, 1989, 1991). This showed that simultaneous ingestion of grapefruit juice with the calcium channel blocker felodipine significantly increases the bioavailability of felodipine. As a result, blood pressure can be lowered more and heart rate increased. The phenomenon has since been investigated in numerous other studies.
Mechanism of interaction
Grapefruit juice is a potent inhibitor of the enzyme CYP3A4 in the intestine, thus inhibiting the presystemic metabolism of pharmaceutical agents. However, it has no effect on metabolism in the liver (possibly at high doses). There are two possible consequences of this. First, inhibition of metabolism may allow more active drug to enter the organism, increasing bioavailability and leading to enhanced pharmacological and toxic effects. An example of this is felodipine, which is inactivated in the intestine by CYP3A4 to a relevant extent. Patient information draws attention to this fact: “Do not take with grapefruit juice, as this may result in an increased effect.” Second, prodrugs that are metabolized in the intestine by CYP3A4 may not exert their effects in the body. However, this second case is of less practical importance. Grapefruit juice also appears to be an inhibitor or activator of the efflux transporter P-glycoprotein and to inhibit intestinal OATP. P-glycoprotein provides a transport barrier for many drugs. Inhibition of OATP causes less drug to be absorbed because OATP promotes the uptake of its substrates into the bloodstream (examples: fexofenadine, talinolol, aliskiren). Studies have shown that ingestion of 250 ml (1 glass) of grapefruit juice is sufficient to trigger interactions for about 24 hours. Only after 3 days the metabolism has normalized. Grapefruit juice irreversibly (suicide inhibition) and reversibly inhibits CYP. It is a weaker inhibitor than, for example, ketoconazole and ritonavir, which additionally also suppress metabolimus in the liver. Which ingredients are responsible for the effects is still a matter of debate, as study results are conflicting. It must also be noted that grapefruit juice is not a sharply defined substance, but consists of myriad ingredients that vary depending on variety, growing conditions, and manufacturing process. Candidates include furanocoumarins, flavonoids and glycosides.
Active ingredients of concern
These considerations make it clear that an active pharmaceutical ingredient must meet certain requirements for an interaction to occur:
- Substrate of CYP3A4 and/or of P-glycoprotein or of OATP in the gut.
- Low bioavailability due to relevant intestinal metabolism.
- Metabolic inactivation or activation (less common).
These criteria apply partially or completely to numerous practice-relevant agents, for example, felodipine, benzodiazepines (midazolam, diazepam), antiepileptics (carbamazeppine), immunosuppressants (cyclosporine, everolimus, tacrolimus), HIV protease inhibitors (saquinavir), antihistamines (terfenadine, a. H. ), anxiolytics (buspirone), SSRIs (sertraline), antiarrhythmics (amiodarone, dronedarone)., prokinetics (cisapride), and statins (eg, simvastatin).
Conclusion for Practice
Grapefruit juice, as a moderately potent inhibitor of CYP3A4 in the gut, has the potential to cause drug-drug interactions, trigger adverse effects, or, in rarer cases, reduce drug efficacy. The effect is dose and concentration dependent: The higher and more concentrated the juice, the stronger the inhibition. The practical relevance is subject to debate and is not undisputed in the literature. We consider it advisable to refrain from consuming grapefruit juice during therapy with corresponding drugs as a precaution. The practical relevance has to be evaluated for each active substance individually. For example, the interaction with sildenafil probably does not lead to a risk for the patient, but should be avoided as a precaution (Jetter et al., 2002).