Interactions between grapefruit juice and psychotropic medications: an update of the literature and an original case series

ABSTRACT

Introduction

There is a large body of preclinical data implicating that grapefruit juice (GJ) inhibits many CYP 450 isoforms. The potential of GJ-to-drug is of high relevance to clinical psychiatry, because a wide range of psychotropic medicines undergo CYP 450 metabolism and P-gp transport.

Areas covered

Relevant data were identified by searching the electronic databases up to February 2024. This work constitutes a summary of preclinical and clinical data on GJ impact on CYP 450 metabolism, P-glycoprotein, and organic anion-transporting polypeptides (OATPs), with focus on studies that assessed GJ-to-psychotropic drug interactions. Additionally, an unpublished case series of nine patients is provided.

Expert opinion

The impact of GJ on CYP 3A4 appears to be the critical mechanism for the majority of GJ-to-psychopharmacotherapy interactions described in human studies or case reports. However, there are studies and cases of patients clearly showing that this is not the only route explaining the GJ effect, and at times, this particular is of no relevance and that other CYP 450 isoforms as well as drug transporting proteins might be involved. The risk of GJ-to-psychotropic drugs needs to be further evaluated in a ‘real-world’ setting and apply not only measures of pharmacokinetics but also treatment effectiveness and safety.

KEYWORDS:

• Grapefruit juice
• CYP 450
• OATP
• P-glycoprotein
• food-to-drug interactions
• psychopharmacology

Article highlights

• Grapefruit juice contains bioactive compounds (furanocoumarins and flavonoids), which may alter psychotropic drug transport by OATPs and P-gp, as well as CYP 450 metabolism.

• Preclinical studies indicate that grapefruit juice may influence many CYP 450 isoforms, but the majority of these were not replicated in human studies.

• Data from human trials and case reports show that grapefruit juice may cause clinically significant interactions, especially with psychotropic drugs metabolized via CYP 3A4 and CYP 2C19.

• Psychotropic medications that are of highest risk of interaction with grapefruit juice are those characterized by narrow therapeutic window and low bioavailability, as well as substrates of CYP 3A4 or CYP 2C19 metabolism and P-gp transport.

• Significant pharmacokinetic interactions of grapefruit juices were noted in human studies in which participants received diazepam, triazolam, midazolam, fluvoxamine, sertraline, and carbamazepine or in case reports of treatment with methadone, trazodone + fluoxetine, agomelatine, duloxetine, escitalopram, mirtazapine, mianserin, fluoxetine, sertraline + zolpidem, sertraline + estazolam, sertraline + doxylamine, and quetiapine.

• Other fruit, especially citrus, juices might also have an impact on psychotropic drug transport and metabolism.

Declaration of interest

M. Siwek reports a relationship with: Lundbeck LLC that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement, Angelini Pharma that includes: consulting or advisory, funding grants, speaking and lecture fees, and travel reimbursement. Gedeon Richter Plc that includes: speaking and lecture fees and travel reimbursement, G.L Pharma GmbH that includes: speaking and lecture fees, Adamed Pharma S.A. that includes: speaking and lecture fees, Viatris that includes: consulting or advisory, speaking and lecture fees and travel reimbursement, KRKA Pharmaceuticals that includes: speaking and lecture fees, Pfizer Inc. that includes: speaking and lecture fees, Bausch Health Poland Sp. z o.o. that includes: speaking and lecture fees, Celon Pharma that includes: consulting or advisory and speaking and lecture fees, Zentiva Polska Sp. z o.o. that includes: speaking and lecture fees and travel reimbursement, EGIS Polska Sp. z o.o. that includes: speaking and lecture fees, Janssen Pharmaceuticals Inc that includes: speaking and lecture fees, Sandoz Polska Sp. z o.o. that includes: speaking and lecture fees, Mylan Pharmaceuticals Inc that includes: speaking and lecture fees, Sanofi that includes: speaking and lecture fees, Swixx Biopharma SA that includes: speaking and lecture fees. A Krupa reports a relationship with: Angelini Pharma that includes: consulting or advisory, funding grants, consulting or advisory and travel reimbursement Gedeon Richter Plc that includes: travel reimbursement, Sandoz Polska Sp. z o.o. that includes: travel reimbursement, Zentiva Polska Sp. z o.o. that includes: travel reimbursement, Lundbeck LLC that includes: travel reimbursement, Sanofi that includes: consulting or advisory. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.