Ms. H, age 42, was given a diagnosis of bipolar disorder 10 years ago and has been taking carbamazepine, 1,200 mg/d, and olanzapine, 10 mg/d, for the past 2 years. She has not experienced a mood episode while on this regimen, and her carbamazepine level was 9.2 μg/mL 6 months ago. The only adverse effect she experienced was weight gain of approximately 10 lb. Ms. H takes a calcium supplement, but no other medications.
Ms. H reports to her psychiatrist that, for the past few days, she has been feeling nauseated, fatigued, and dizzy, but has continued taking her medications as prescribed. Her carbamazepine level is found to be 13.1 μg/mL. Ms. H states she has not started any new medications or supplements; her serum creatinine and liver function test results are within normal limits.
Upon further questioning, Ms. H says that an upper respiratory infection has been “going around her office,” so she increased her vitamin C intake by drinking 2 glasses of grapefruit juice a day (she doesn’t like orange juice). She has heard grapefruit juice can cause problems with some drugs so she is careful not to drink it at the same time she takes her medications. Her psychiatrist recognizes there may be a drug interaction involved, and recommends Ms. H hold her carbamazepine for 1 day and not consume any more grapefruit juice. A few days later, she reports feeling much better during a follow-up call and she makes an appointment to have her carbamazepine level rechecked in a we
Although grapefruit products are high in vitamins and low in calories, they can be associated with potentially serious drug interactions. The interaction between grapefruit juice and the calcium channel blocker felodipine was discovered inadvertently >20 years ago; since that time, possible interactions with >85 medications have been identified.1 Interactions with grapefruit products are complicated because, although most result in increased drug exposure, reduced exposure of the medication also can occur. Additionally, the degree and clinical significance of the interaction varies among individuals and from one drug to another.
Mechanism of action
Most interactions with grapefruit products are thought to result from the inhibition of intestinal cytochrome P450 3A4 (CYP3A4). CYP3A4 is involved in the metabolism of numerous drugs, and is the most abundant cytochrome P450 enzyme in the liver and epithelial cells lining the intestine.2 Although hepatic CYP3A4 is thought to be minimally affected by grapefruit, inhibition of intestinal CYP3A4 can result in an overall increase in bioavailability of medications that are substrates and raise the risk of potential toxicity.3 Grapefruit contains various chemicals collectively known as furanocoumarins, which are largely responsible for inhibition of intestinal CYP3A4.4 Additionally, Seville oranges and the pomelo (a large, sweet grapefruit-like citrus fruit) also contain furanocoumarins and could have a similar effect, warranting caution with certain medications.5
Inhibition of CYP3A4 by furanocoumarins cannot be reversed, and new enzymes must be synthesized to return to the previous level of function.6 Therefore, drug interactions resulting from CYP3A4 inhibition can last for as long as 72 hours after ingesting grapefruit products.7 Separating consumption of grapefruit products and medication administration will not help manage this interaction.
Grapefruit products also could affect drug disposition through effects on various drug transporters. Decreased systemic exposure to certain medications could occur through grapefruit’s inhibition of organic anion-transporting polypeptides (OATPs). OATPs form a family of drug uptake transporters found in the intestine, liver, kidney, and brain.8 For drugs that are substrates of OATPs, grapefruit’s inhibition of this transporter can result in decreased absorption and a resulting decrease in efficacy. Flavanoids in grapefruit, such as naringin, inhibit OATPs, which is competitive in nature.9 Unlike the irreversible inhibition of CYP3A4 by furanocoumarins, flavanoids effects on OATPs have been shown to decrease within 4 hours.10
No psychotropic medications have been identified as being susceptible to this interaction, but for those medications affected—including fexofenadine and levothyroxine—separating consumption of grapefruit and medication administration by 4 hours could avoid this interaction.11 Additional data indicate that orange juice and apple juice could have similar effects on OATPs.12
Perhaps the most well-known drug transporter, P-glycoprotein is part of the multidrug-resistant subfamily of transporters. It is located throughout the body, including in the intestine, kidneys, liver, and blood-brain barrier. P-glycoprotein acts as an export pump to decrease the cellular concentration of many different drug substrates, and many agents can alter P-glycoprotein’s expression or function.
Small changes in P-glycoprotein’s activity can result in substantial changes in the disposition of substrates, which can include certain antineoplastics and antiretrovirals. Most reports have found grapefruit juice inhibits P-glycoprotein-mediated efflux; however, there also are reports of transporter activation.6 Additionally, P-glycoprotein and CYP3A4 share many substrates, so it can be difficult to isolate the contribution of P-glycoprotein to grapefruit−drug interactions.13 The effect of grapefruit on P-glycoprotein activity has been difficult to fully elucidate; more studies are needed.