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Juice interactions: What patients need to know

Maria G. Tanzi

M ore than 85 medications are known to interact with grapefruit juice, and approximately one-half of these interactions have the potential

to cause serious adverse events. In addition, many medications can inter- act with other juices, such as orange, apple, and cranberry. For example, the Drug Facts label of OTC fexofenadine (Allegra—Sanofi) states not to consume the drug with fruit juices.

Many patients are unaware that fruit juices can cause significant drug

that then bond covalently to the active site of the enzyme, causing irreversible inactivation. This leads to increased bioavailability of administered medica-

tions that are substrates for intestinal CYP3A4 and creates the potential for toxic effects. Since grapefruit primarily targets

intestinal CYP3A4, not liver CYP3A4, I.V. medications are usually not affect- ed. Grapefruit products also interact with the efflux transporter P-glycopro- tein and uptake transporters such as organic anion-transporting polypep- tides (OATPs).

Other juices

Seville oranges, limes, and pomelos produce drug interactions similar to grapefruit by inhibiting intestinal CYP- 3A4. Other juices, such as orange and apple, appear to inhibit OATPs, which aid in drug absorption. OATP inhibi- tion results in reduced absorption and potentially decreased serum levels of drugs transported by OATP. Drug interactions with cranberry juice have also been reported. These interactions have primarily occurred

been reported. These interactions have primarily occurred ■ Grapefruit, orange, apple, and cranberry juices have
■ Grapefruit, orange, apple, and cranberry juices have all been associated with drug interactions. ■
■ Grapefruit, orange, apple,
and cranberry juices have all
been associated with drug
■ Separation of medications
and grapefruit products by a
few hours is usually not
helpful in avoiding drug

interactions. Pharmacists must educate patients about this fact to decrease the likelihood of these events.

Interaction mechanisms


The irreversible inhibition of intestinal cytochrome P450 (CYP)3A4 enzymes by grapefruit juice is the most common- ly identified mechanism mediating grapefruit drug interactions. CYP3A4 metabolizes furanocoumarins found in grapefruit to reactive intermediates

Table 1. Medications with a very high grapefruit interaction risk

Interacting drugs (generic name)

Dose-related adverse events


Postural hypotension, syncope






Torsades de pointes


Gangrene, stroke

Oral ketamine

Respiratory depression


Torsades de pointes, orthostatic hypotension, syncope

Source: Bailey DG et al. Grapefruit-medication interactions: forbidden fruit or avoidable consequences [published online ahead of print November 26, 2012]? CMAJ.

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with warfarin, and the exact mecha- nism is unknown. According to one mechanism proposed by research-

ers, cranberry flavonoids interact with

CYP450 enzymes, resulting in reduced warfarin metabolism. Others have at- tributed cranberry–warfarin interac- tions to the presence of salicylic acid in cranberries, which results in an in- creased bleeding risk.

High-risk patients and likely interactions

All forms of grapefruit, including fresh-

ly squeezed juice, frozen concentrate, and whole fruit, can reduce the activ-

ity of intestinal CYP3A4. As little as 200

mL of grapefruit juice, the amount in a

whole grapefruit, may be sufficient to cause clinically relevant increased sys- temic drug concentrations and subse- quent adverse events. In addition, since administration of grapefruit causes

irreversible inactivation, the effects of consuming these products can last as long as 72 hours. Therefore, separation of medications and grapefruit products by a few hours is usually not helpful. For OATP-mediated fruit juice in- teractions, the magnitude of the effects of orange and apple juices on OATP ap- pear to be similar and can be significant with a 200-mL serving. Currently, there is minimal to no evidence that eating these fruits causes clinically significant OATP-mediated drug interactions. The inhibition of OATP appears to dissipate over a shorter time period than inhibi- tion of intestinal CYP3A4. These types of interactions may be avoided by sepa- rating medication and juice consump-

tion by at least 4 hours.

Patients older than 45 years have been noted as a key patient group vul- nerable to grapefruit drug interactions

in the literature. This patient population is most likely to purchase grapefruits

and to have comorbidities which require

multiple medications. Older patients are

also at high risk for clinically significant

fruit juice interactions because pharma- cokinetics are different in patients older than 70 years, and in general, the body’s compensatory mechanisms do not work as effectively as one ages. David Bailey, PhD, and colleagues

fruit juices

Table 2. Medications with a high grapefruit interaction risk

Interacting drugs (generic name)

Dose-related adverse events

Anticancer agents


Torsades de pointes, myelotoxicity


Torsades de pointes, myelotoxicity




Myelotoxicity, nephrotoxicity


Torsades de pointes, myelotoxicity


Torsades de pointes, myelotoxicity


Torsades de pointes, myelotoxicity


Torsades de pointes, myelotoxicity


Torsades de pointes, myelotoxicity

Anti-infective agents


Torsades de pointes




Torsades de pointes


Torsades de pointes

Antilipid agent



Cardiovascular agents Amiodarone

Torsades de pointes


Gastrointestinal bleeding


Gastrointestinal bleeding


Loss of efficacy


Hyperkalemia, serious arrhythmias


Gastrointestinal or kidney bleeding


Complete heart block

Central nervous system agents Buspirone

Dizziness, sedation


Hallucinations, somnolence Respiratory depression

Oral fentanyl


Respiratory depression


Torsades de pointes


Dizziness, somnolence


Torsades de pointes

Gastrointestinal agent Cisapride

Torsades de pointes

Immunosuppressant agents Cyclosporine



Myelotoxicity, nephrotoxicity


Myelotoxicity, nephrotoxicity



Source: Bailey DG et al.

Table 3. OATP-mediated fruit juice interactions


Decrease in absorption






Approximately 60%


Approximately 20%


Approximately 40%







Abbreviation used: OATP, organic anion-transporting polypeptide Source: Cupp M. OATP fruit juice drug interactions. Pharmacist’s Letter/Prescriber’s Letter. June 2011.

published an updated list of drugs that interact with grapefruit, their predicted interaction risk (e.g., very high, high, or intermediate), and potential dose-relat- ed adverse events in the Canadian Medi- cation Association Journal in November 2012. A summary of drugs in the very high and high risk categories is pre- sented in Tables 1 and 2, respectively; these tables are not all inclusive. Researchers have described OATP- mediated fruit juice interactions with grapefruit, orange, and apple juices in other publications as well. A summary of select medications involved in these types of interactions is presented in Table 3. The absorption of some medi- cations is decreased by less than 10%, which is not thought to be clinically significant in most patients.

Patient counseling pearls

FDA has released an educational piece listing tips for patients regarding po- tential fruit juice interactions (www.

dates/ucm292276.htm). These informa- tional points include the following:

Educate patients to ask a pharma- cist or other health care provider if they can drink grapefruit and other juices with prescribed medications.

Encourage patients to read the Medication Guide or patient infor- mation sheet that comes with pre- scription medications to identify any fruit juice interactions.

Encourage patients to review the Drug Facts labels on nonprescrip- tion medications for fruit juice in- teractions.

If patients must avoid certain fruit juices, educate them to check the labels of flavored drinks to ensure that they do not contain those juices.

Educate patients on other fruits that

should be avoided, such as Seville oranges and tangelos, with medica- tions known to interact with grape- fruit. Pharmacists and health profession- als who properly screen for and edu- cate patients about potential fruit juice interactions can help minimize their occurrence and reduce the likelihood of adverse events.

Maria G. Tanzi, PharmD Contributing writer, Pharmacy Today

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