Savvy Psychopharmacology Grapefruit juice and psychotropics: How to avoid potential interactions Danielle L. Bishop, PharmD, BCPP s. H, age 42, was given a diagnosis she reports feeling much better during a fol- of bipolar disorder 10 years ago and low-up call and she makes an appointment Mhas been taking carbamazepine, to have her carbamazepine level rechecked 1,200 mg/d, and olanzapine, 10 mg/d, for the in a week. past 2 years. She has not experienced a mood episode while on this regimen, and her car- Although grapefruit products are high in bamazepine level was 9.2 μg/mL 6 months vitamins and low in calories, they can be Vicki L. Ellingrod, ago. The only adverse effect she experienced associated with potentially serious drug PharmD, FCCP was weight gain of approximately 10 lb. interactions. The interaction between Department Editor Ms. H takes a calcium supplement, but no grapefruit juice and the calcium channel other medications. blocker felodipine was discovered inad- Ms. H reports to her psychiatrist that, for vertently >20 years ago; since that time, the past few days, she has been feeling nau- possible interactions with >85 medica- seated, fatigued, and dizzy, but has contin- tions have been identified.1 Interactions ued taking her medications as prescribed. with grapefruit products are complicated Her carbamazepine level is found to be 13.1 μg/mL. Ms. H states she has not started Practice Points any new medications or supplements; her • In general, an entire grapefruit or 8 oz serum creatinine and liver function test of juice is enough to alter a susceptible results are within normal limits. drug’s pharmacokinetics. Upon further questioning, Ms. H says • Several drug-specific characteristics can that an upper respiratory infection has been help identify risk of a clinically relevant “going around her office,” so she increased interaction with grapefruit, including her vitamin C intake by drinking 2 glasses low bioavailability, metabolism through of grapefruit juice a day (she doesn’t like CYP3A4, oral administration, and a narrow orange juice). She has heard grapefruit juice therapeutic index. can cause problems with some drugs so she • Grapefruit most commonly causes an is careful not to drink it at the same time increase in concentration of certain Savvy Psychopharmacology she takes her medications. Her psychiatrist oral medications through inhibition is produced in partnership recognizes there may be a drug interaction of intestinal cytochrome 3A4 enzymes; with the College involved, and recommends Ms. H hold her however, grapefruit also has been shown of Psychiatric to decrease the concentration of specific and Neurologic carbamazepine for 1 day and not consume drugs through inhibition of organic anion- Pharmacists any more grapefruit juice. A few days later, cpnp.org transporting polypeptides. mhc.cpnp.org (journal) Dr. Bishop is a Clinical Pharmacy Specialist, Department of Pharmacy, Rush University Medical Center, Chicago, Illinois. • Interactions with grapefruit-containing products may apply only to specific Disclosure The author reports no financial relationships with any company medications within a therapeutic category Current Psychiatry whose products are mentioned in this article or with manufacturers and are not necessarily a “class effect.” 60 June 2015 of competing products. Savvy Psychopharmacology because, although most result in increased substrates of OATPs, grapefruit’s inhibition drug exposure, reduced exposure of the of this transporter can result in decreased medication also can occur. Additionally, absorption and a resulting decrease in effi- the degree and clinical significance of the cacy. Flavanoids in grapefruit, such as nar- interaction varies among individuals and ingin, inhibit OATPs, which is competitive from one drug to another. in nature.9 Unlike the irreversible inhibi- tion of CYP3A4 by furanocoumarins, flava- Mechanism of action noids effects on OATPs have been shown Most interactions with grapefruit products to decrease within 4 hours.10 are thought to result from the inhibition of No psychotropic medications have intestinal cytochrome P450 3A4 (CYP3A4). been identified as being susceptible to CYP3A4 is involved in the metabolism of this interaction, but for those medications numerous drugs, and is the most abun- affected—including fexofenadine and Clinical Point dant cytochrome P450 enzyme in the liver levothyroxine—separating consumption Drug interactions and epithelial cells lining the intestine.2 of grapefruit and medication administra- Although hepatic CYP3A4 is thought to tion by 4 hours could avoid this interac- resulting from be minimally affected by grapefruit, inhi- tion.11 Additional data indicate that orange CYP3A4 inhibition bition of intestinal CYP3A4 can result in juice and apple juice could have similar can last for as long an overall increase in bioavailability of effects on OATPs.12 as 72 hours after medications that are substrates and raise Perhaps the most well-known drug ingesting grapefruit the risk of potential toxicity.3 Grapefruit transporter, P-glycoprotein is part of the contains various chemicals collectively multidrug-resistant subfamily of trans- products known as furanocoumarins, which are porters. It is located throughout the body, largely responsible for inhibition of intes- including in the intestine, kidneys, liver, tinal CYP3A4.4 Additionally, Seville and blood-brain barrier. P-glycoprotein oranges and the pomelo (a large, sweet acts as an export pump to decrease the grapefruit-like citrus fruit) also contain cellular concentration of many different furanocoumarins and could have a simi- drug substrates, and many agents can alter lar effect, warranting caution with certain P-glycoprotein’s expression or function. medications.5 Small changes in P-glycoprotein’s activ- Inhibition of CYP3A4 by furanocouma- ity can result in substantial changes in the rins cannot be reversed, and new enzymes disposition of substrates, which can include must be synthesized to return to the pre- certain antineoplastics and antiretrovi- vious level of function.6 Therefore, drug rals. Most reports have found grapefruit interactions resulting from CYP3A4 inhi- juice inhibits P-glycoprotein-mediated bition can last for as long as 72 hours after efflux; however, there also are reports ingesting grapefruit products.7 Separating of transporter activation.6 Additionally, consumption of grapefruit products and P-glycoprotein and CYP3A4 share many medication administration will not help substrates, so it can be difficult to iso- manage this interaction. late the contribution of P-glycoprotein to Grapefruit products also could affect grapefruit−drug interactions.13 The effect drug disposition through effects on vari- of grapefruit on P-glycoprotein activity Discuss this article at ous drug transporters. Decreased systemic has been difficult to fully elucidate; more www.facebook.com/ CurrentPsychiatry exposure to certain medications could studies are needed. occur through grapefruit’s inhibition of organic anion-transporting polypeptides Grapefruit consumption (OATPs). OATPs form a family of drug and its effect uptake transporters found in the intestine, Drug interactions can occur by consum- Current Psychiatry liver, kidney, and brain.8 For drugs that are ing commercially produced grapefruit Vol. 14, No. 6 61 Savvy Psychopharmacology juice and juice from concentrate, as well as changes caused by a grapefruit interac- freshly squeezed juice and grapefruit seg- tion could vary based on interindividual ments.14 CYP3A4-inhibiting furanocouma- differences. The amount and activity of rins also have been isolated in grapefruit intestinal CYP3A4 can vary from per- peel; it is not known, however, whether son to person, and can be influenced by items made from peel (marmalade, can- genetic polymorphisms in addition to died peel) contain concentrations high race, age, and environmental variables.18 enough to pose a risk of a drug interac- Interindividual sensitivity to a change in tion.14 Contributing to the unpredictabil- a drug’s concentration also will differ, and ity of grapefruit-drug interactions, the patient-specific factors, such as concomi- amount or concentration of furanocou- tant drugs or diseases, could influence the marins can vary among grapefruit prod- likelihood of harm. Clinical Point ucts and brands.15 This variability can be Interactions with grapefruit products The effect of influenced by the variety or maturity of are not necessarily a “class effect,” and the fruit and the fruit’s exposure to envi- specific drugs within a therapeutic cat- grapefruit on ronmental stress.4 egory can be affected (although others P-glycoprotein The frequency of consuming a grape- might not). Several drug-specific charac- activity has been fruit product can influence the degree of teristics can help gauge the risk of a clini- difficult to fully a drug interaction. In general, consum- cally relevant interaction with grapefruit, ing one 8-oz glass of grapefruit juice or including: elucidate; more the segments from a whole grapefruit is • metabolism through CYP3A4 studies are needed enough to alter a susceptible drug’s phar- • low bioavailability macokinetics.14 Regular grapefruit product • oral administration consumption, however, can result in an • a narrow therapeutic index.1 overall greater effect.16,17 For drugs with low bioavailability Lilja et al16 conducted a randomized, because of first-pass metabolism, grape- 4-phase, crossover study to look at the fruit’s inhibition of intestinal