Grapefruit juice and psychotropics: How to avoid potential interactions

Grapefruit consumption and its effect
Drug interactions can occur by consum­ing commercially produced grapefruit juice and juice from concentrate, as well as freshly squeezed juice and grapefruit seg­ments.¹⁴ CYP3A4-inhibiting furanocouma­rins also have been isolated in grapefruit peel; it is not known, however, whether items made from peel (marmalade, can­died peel) contain concentrations high enough to pose a risk of a drug interac­tion.¹⁴ Contributing to the unpredictabil­ity of grapefruit-drug interactions, the amount or concentration of furanocou­marins can vary among grapefruit prod­ucts and brands.¹⁵ This variability can be influenced by the variety or maturity of the fruit and the fruit’s exposure to envi­ronmental stress.⁴

The frequency of consuming a grape­fruit product can influence the degree of a drug interaction. In general, consum­ing one 8-oz glass of grapefruit juice or the segments from a whole grapefruit is enough to alter a susceptible drug’s phar­macokinetics.¹⁴ Regular grapefruit product consumption, however, can result in an overall greater effect.^16,17

Lilja et al¹⁶ conducted a randomized, 4-phase, crossover study to look at the effect of grapefruit juice dose on kinetics of triazolam. Grapefruit juice was found to increase the mean area under the concentration-time curve (AUC) of tri­azolam compared with water, but no dif­ference was found between single glasses of normal-strength and double-strength grapefruit juice. However, repeated consumption of double-strength grape­fruit juice (200 mL, 3 times/d for 3 days) increased triazolam’s mean AUC by 143%, compared with an increase of 49% with just a single 200-mL glass of double-strength juice.¹⁶ Recurrent consumption of grapefruit juice (8 oz, 3 times/d for 6 days) also was found to increase the kinetics of the antihypertensive felodipine more than a single glass of grapefruit juice.¹⁷

Clinical consequences of an interaction between a drug and grapefruit can be difficult to predict. Drug concentration changes caused by a grapefruit interac­tion could vary based on interindividual differences. The amount and activity of intestinal CYP3A4 can vary from per­son to person, and can be influenced by genetic polymorphisms in addition to race, age, and environmental variables.¹⁸ Interindividual sensitivity to a change in a drug’s concentration also will differ, and patient-specific factors, such as concomi­tant drugs or diseases, could influence the likelihood of harm.

Interactions with grapefruit products are not necessarily a “class effect,” and specific drugs within a therapeutic cat­egory can be affected (although others might not). Several drug-specific charac­teristics can help gauge the risk of a clini­cally relevant interaction with grapefruit, including:
• metabolism through CYP3A4
• low bioavailability
• oral administration
• a narrow therapeutic index.¹

For drugs with low bioavailability because of first-pass metabolism, grape­fruit’s inhibition of intestinal CYP3A4 can result in a greater relative increase in plasma concentrations compared with a drug with high bioavailability.¹⁹

For example, an increase in bioavailabil­ity from 5% to 10% will result in a much larger increase in AUC and overall clinical exposure compared with an increase from 85% to 90% even though both represent an absolute increase of 5%. Although a drug does not have to have low oral bioavail­ability for an interaction to occur, lower bioavailability means that a drug has a higher likelihood of causing a significant interaction because of altered pharmaco­kinetics. Of note, injectable medications will not interact with grapefruit because metabolism through intestinal CYP3A4 is bypassed and grapefruit does not signifi­cantly inhibit hepatic CYP3A4.

Although grapefruit products could alter the pharmacokinetics of susceptible drugs, those changes might not be associated with adverse effects. Therefore, a factor to con­sider in evaluating a potential interaction with grapefruit is the drug’s therapeutic index and its risk of serious adverse effects. Drugs with a narrow therapeutic index are of particular concern because a significant increase in therapeutic or adverse effects could result from a relatively small increase in the drug’s concentration.⁷

Which medications are affected?
Among medications identified as interact­ing with grapefruit, some cardiovascular agents and several of the HMG-CoA reduc­tase inhibitors (statins) have garnered the most attention. However, grapefruit also can affect the metabolism of several psy­chotropic medications through inhibition of intestinal CYP3A4 (Table).^16,20-35 Prescribing information for some drugs warns against consuming grapefruit while using the medication. Among CNS agents, buspirone, carbamazepine, lurasidone, pimozide, triazolam, and oral midazolam all have such warnings in their product labeling.

Buspirone currently is not recommended with “large quantities of grapefruit juice.”²⁰ A randomized, 2-phase crossover study looking at the effects of grapefruit juice on buspirone’s pharmacokinetics found that double-strength grapefruit juice (200 mL, administered 3 times/d for 3 days) resulted in a 9.2-fold increase in mean AUC and a 4.3-fold increase in mean Cmax after a single 10-mg buspirone dose.22 Highlighting the wide interindivid­ual variability seen with drug-grapefruit interactions, the increase found in buspi­rone’s AUC ranged from 3-fold to 20-fold among study participants.²²