Q: What is the significance of grapefruit-drug interactions, and how can I most effectively detect if a patient is at risk for negative therapeutic outcomes due to this type of interaction?
A: Grapefruit is a widely known inhibitor of the CYP450-mediated metabolism of drugs. Inhibition may result in increased parent drug concentrations or altered metabolite formation, leading to toxicity associated with elevated serum drug levels or therapeutic failure if a patient is taking a prodrug. Grapefruit contains substances known as furanocoumarins, which are capable of inhibiting CYP3A4 enzymes responsible for drug metabolism.
Grapefruit products are well-known culprits of drug-food interactions that occur in clinical practice. In particular, grapefruit has demonstrated the ability to cause CYP450 3A4 inhibition. CYP3A4 is one of the primary enzymes involved in the metabolism of a multitude of medications. This metabolic pathway is primarily involved in metabolism of medications to inactive metabolites. Subsequently, inhibition of this pathway can lead to increased plasma levels of parent drug, possibly potentiating the effects of the drug. As plasma levels increase, so does the opportunity for adverse effects associated with prescribed therapy. Pharmacokinetic studies have been widely performed to establish this interaction.1
Several medications used in pain management are affected by grapefruit-drug interactions. A study of patients receiving maintenance methadone therapy was performed to determine the effect of grapefruit juice on steady state methadone concentrations. Statistically significant increases in serum concentrations of methadone were observed.2,3 Elevated serum concentrations could lead to an increased risk of adverse effects such as central nervous system (CNS) depression and cardiotoxicity, especially in those patients that are naive to therapy.
A similar study detailed the effect of 3A4 inhibition on oxycodone and formation of its metabolites (Figure 1).4 After five days of grapefruit juice and oxycodone ingestion, serum oxycodone and oxymorphone concentrations were increased by 67% and 32%, respectively. Collectively, the results indicated a shift toward the CYP2D6 metabolic pathway caused by reduced CYP3A4 activity. Subjects reported increased impairment from oxycodone and grapefruit co-ingestion, possibly due to an escalation in serum concentrations of both parent drug and its active metabolite, oxymorphone.
Figure 1: Oxycodone cytochrome P450 metabolic pathway
The group of compounds found in grapefruit that have been identified as contributing to CYP3A4 inhibition are known as furanocoumarins. A number of these compounds exist, but 6’7’ dihydroxybergamottin (DHB), bergamottin, and bergaptol are found at the highest concentrations in grapefruit and grapefruit juice.5 A number of studies have verified that these compounds are capable of inhibiting CYP3A4 enzymes and may do so in a dose-dependent manner.6,7 A recent series of studies have shown that bergamottin is not readily detectable in urine due to extensive metabolism to the metabolites DHB and bergaptol.5,8 Aegis has been performing longitudinal surveillance studies of these compounds and obtained results consistent with these studies. Moving forward, Aegis Drug-Drug Interaction Testing now includes testing for both DHB and bergaptol in place of naringenin and neohesperedin (Grapefruit Flavonoids). This change was made to improve the sensitivity and specificity of our test offering.
Detection of grapefruit markers may occur during a DDI analysis, revealing potential drug-food interactions with other substances identified in a urine sample. If an interaction is detected, effects associated with concurrent ingestion of the positive analyte and grapefruit are reported. This information is intended to supplement the knowledge of healthcare providers during patient assessment and assist in clinical decision making in regard to pharmacotherapy. Of note, there is a possibility that the presence of one or more of these markers may be from ingestion of a substance other than grapefruit (such as lime or parsley), or of a substance containing grapefruit juice as an ingredient, of which the patient may be unaware. Table 1 below offers a compilation of beverages containing grapefruit juice and foods that contain furanocoumarins.9,10 Each positive result for DHB and/or bergaptol should prompt further assessment of a patient’s diet to determine the likelihood of the grapefruit-drug interaction identified during a DDI analysis.
NOTICE: The information above is intended as a resource for health care providers. Providers should use their independent medical judgment based on the clinical needs of the patient when making determinations of who to test, what medications to test, testing frequency, and the type of testing to conduct.
1. Bailey DG, Arnold JMO, Spence JD. Grapefruit juice and drugs: how significant is the interaction? Clin Pharmacokin. Feb 1994;26(2):91-8.
2. Benmebarek M, Devaud C, Gex-Fabry M, et al. Effects of grapefruit juice on the pharmacokinetics of the enantiomers of methadone. Clin Pharmacol Ther. Jul 2004;76(1):55-63.
3. Chang Y, Fang WB, Lin SN, Moody DE. Stereo-selective metabolism of methadone by human liver microsomes and cDNA-expressed cytochrome P450s: a reconciliation. Basic Clin Pharmacol Toxicol. Jan 2011;108(1):55-62
4. Nieminen TH, Hagelberg NM, Saari TI, et al. Grapefruit juice enhances the exposure to oral oxycodone. Basic Clin Pharmacol Toxicol. Oct 2010;107(4):782-788.
5. Melough M, Vance TM, Lee SG, et al. Furocoumarin kinetics in plasma and urine of healthy adults following consumption of grapefruit (citrus paradise macf.) and grapefruit juice. J. Agric. Food Chem. 2017; 65: 3006-12.
6. Girennavar B, Poulose SM, Jayaprakasha GK, Bhat NG, Patil BS. Fouranocumarins from grapefruit juice and their effect on human CYP 3A4 and CYP 1B1 isoenzymes. Bioorg Med Chem. 2006: 14: 2606-12.
7. Girennavar B, Jayaprakasha GK, Jadegoud Y, Gowda GAN, Patil BS. Radical scavenging and cytochrome P450 3A4 inhibitory activity of bergaptol and geranylcoumarin from grapefruit. Bioorg Med Chem. 2017;15:3684-91.
8. Lee SG, Kim k, Vance TM, et al. Development of a comprehensive analytical method for furanocoumarins in grapefruit and their metabolites in plasma and urine using UPLC-MC/MC: a preliminary study. Int. J. Food Sci. Nutr. Jul 2016; 67: 881-7.
9. Auten AA, Beauchamp LN, Joshua T, Hardinger KL. Hidden sources of grapefruit in beverages: potential interactions with immunosuppressant medications. Hosp Pharm. 2013;48(6):489-493
10. Melough MM, Lee SG, Cho E, Kim K, Provatas AA, Perkins C. et al. Identification and Quantification of furanocoumarins in popularly consumed foods in the U.S. using QuEChERS extraction coupled with UPLC-MS/MS analysis. J Agric Food Chem. 2017; 65: 5049-55.