Delayed Effect of Grapefruit Juice on Pharmacokinetics and Pharmacodynamics of Tacrolimus in a Living-Donor Liver Transplant Recipient

doi:10.2133/dmpk.21.122

Drug Metabolism and Pharmacokinetics

Volume 21, Issue 2, 2006, Pages 122-125

https://doi.org/10.2133/dmpk.21.122 Get rights and content

Summary:

Tacrolimus is a calcineurin inhibitor that has been widely used to prevent allograft rejection after transplantation. We report a case of a living-donor liver transplant recipient experiencing a considerable increase in the trough blood concentration of tacrolimus after concomitant ingestion of grapefruit juice (250 mL) 4 times for 3 days. The trough blood concentrations of tacrolimus were not changed during or immediate after the repeated intake of grapefruit juice. However, almost 1 week after the final ingestion, the blood concentration of tacrolimus markedly increased to as much as 47.4 ng/mL from 4.7 ng/mL before the ingestion, resulting in a profound reduction of calcineurin phosphatase activity in peripheral blood mononuclear cells. Furthermore, headache and nausea, but not nephrotoxicity or hyperglycemia, took place throughout the period of the elevated blood concentrations. Grapefruit juice may have a clinically significant effect on the pharmacokinetics and pharmacodynamics of tacrolimus. It is recommended to avoid the consumption of grapefruit juice in transplant recipients treated with tacrolimus.

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Cited by (39)

Nirmatrelvir/ritonavir-induced elevation of blood tacrolimus levels in a patient in the maintenance phase post liver transplantation
2024, Journal of Infection and Chemotherapy
Nirmatrelvir is an orally administered anti-SARS-CoV-2 drug used in combination with ritonavir, the drug-metabolizing cytochrome P450 (CYP) 3A inhibitor, to evade metabolism and extend bioavailability. Meanwhile, the immunosuppressant tacrolimus is a CYP3A4/5 substrate, and CYP3A inhibition results in drug-drug interactions. Herein, we report the case of a coronavirus disease 19 (COVID-19) patient in the maintenance phase post liver transplantation, receiving tacrolimus treatment, with a marked increase of blood tacrolimus levels after the initiation of concomitant nirmatrelvir/ritonavir treatment. A 61-year-old Japanese woman underwent a living donor liver transplant for Caroli disease 25 years ago and received tacrolimus 2 mg/day for immunosuppressive treatment. Three days before the observed high tacrolimus blood concentration, she presented to our emergency department with a fever and was diagnosed with COVID-19. She was prescribed an adjusted dose of nirmatrelvir/ritonavir (150 mg/100 mg, twice daily) for 5 days as a high-risk case with immunosuppressive treatment and reduced renal function (estimated glomerular filtration rate, eGFR: 46.6 mL/min/1.73 m²). At the return visit on day 1, blood tacrolimus level was >60 ng/mL on trough sampling, above the upper limit of measurement, with nausea and vomiting as side effects. Tacrolimus treatment was discontinued on the same day. Drug-drug interactions resulting from CYP3A inhibition by nirmatrelvir/ritonavir were deemed responsible for elevated blood tacrolimus levels. Therefore, in liver transplant recipients, tacrolimus dose reduction or discontinuation is required during COVID-19 treatment with nirmatrelvir/ritonavir.
Betel Nut Chewing Is Associated With Reduced Tacrolimus Concentration in Taiwanese Liver Transplant Recipients
2017, Transplantation Proceedings
Studies have shown that arecoline, the major alkaloid component of betel nuts, alters the activity of enzymes in the cytochrome P450 (CYP-450) family. Tacrolimus, an immunosuppressant that protects against organ rejection in transplant recipients, not only is mainly metabolized by CYP3A enzymes but also has a narrow therapeutic range. We aimed to investigate whether dose-adjusted blood trough levels of tacrolimus differed over time between betel nut-chewing and non–betel nut-chewing liver transplant recipients.
In this retrospective case-control study, 14 active betel nut-using liver recipients were matched at a 1:2 ratio to 28 non-betel nut-using liver recipients by sex, age, graft source, duration of follow-up after liver transplantation, and estimated glomerular filtration rate. Differences in liver function index, renal function index, and dose-adjusted blood trough levels of tacrolimus over an 18-month period were compared between the 2 groups by using the Generalized Estimating Equation approach.
Dose-adjusted blood trough levels of tacrolimus tended to be significantly (P = .04) lower in betel nut chewers (mean = 0.81, medium = 0.7, 95% confidence interval [CI] = 0.73 to 0.90) than in nonchewers (mean = 1.12, medium = 0.88, 95% CI = 1.03 to 1.22) during the 18-month study period. However, there was no significant difference in renal and liver function index between the 2 groups.
Liver transplant recipients receiving tacrolimus tend to have lower blood trough levels of the drug over time if they chew betel nuts.
Pharmaceutical consultation for liver transplant patients: A contribution to therapeutic education
2009, Annales Pharmaceutiques Francaises
La consultation pharmaceutique proposée aux patients transplantés hépatiques est l’une des composantes de l’éducation thérapeutique. Le contenu de cette consultation a été défini à partir des résultats des recherches conduites dans le domaine de la communication en santé. Ces travaux incitent à préciser au patient les objectifs de cette consultation, son déroulement, à solliciter son accord et à requérir sa participation dans l’élaboration du plan de traitement. L’étude et la prise en compte des représentations du patient relatives à la transplantation, au traitement et au rejet de son greffon sont indispensables à l’élaboration d’un plan de communication efficace. La mise en œuvre de cette consultation suppose une formation initiale ou continue du pharmacien qui intègre des connaissances en psychologie, sciences cognitives et communication en santé. Elle fait actuellement défaut tant dans la formation initiale que dans la formation continue. Elle devrait être complétée par une mise en pratique et un entraînement au cours des stages hospitaliers et officinaux.
The pharmaceutical consultation offered to liver transplant patients is one of the components of therapeutic education. The content of this consultation has been designed on the basis of research results led in the field of health communication. This research has highlighted the need to clarify to the patient the aims and format of the consultation, to obtain patient approval, and to elicit patient participation in the elaboration of the treatment plan. Studying and taking into account patient representations of transplantation, of transplant treatment and rejection is indispensable to the design of an efficient communication plan. Setting up this consultation requires initial training or continuing vocational training of the pharmacist – this training will address issues in psychology, cognitive science and health communication. No such training is currently available in universities and needs to be set up. It should be followed by practice and training during internships in hospitals and community pharmacies.
Grapefruit-medication interactions: Forbidden fruit or avoidable consequences?
2013, CMAJ. Canadian Medical Association Journal
Citation Excerpt :
In addition, a case report showed cyclosporine concentration to be increased to 600% with grapefruit.44 Taking tacrolimus after ingesting grapefruit juice (250 mL, 4 times/d for 3 d) resulted in a 1000% higher trough blood concentration, causing profound inhibition of calcineurin phosphatase in a recipient of a liver transplant.45 Moreover, taking tacrolimus after consuming a large amount of grapefruit marmalade during the previous week caused a 500% greater blood concentration of the drug and acute renal dysfunction.24
Effect of hepar-protecting Wuzhi capsule on pharmacokinetics and dose-effect character of tacrolimus in healthy volunteers
2022, Biopharmaceutics and Drug Disposition
Drug-Drug Interactions with Over-The-Counter Medicines: Mind the Unprescribed
2022, Therapeutic Drug Monitoring

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Regular ArticleDelayed Effect of Grapefruit Juice on Pharmacokinetics and Pharmacodynamics of Tacrolimus in a Living-Donor Liver Transplant Recipient

Summary:

Lancet

Grapefruit juice-drug interactions

Br. J. Clin. Pharmacol.

The effects of fruit juices on drug disposition: a new model for drug interactions

Eur. J. Clin. Invest.

Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation

Clin. Pharmacokinet.

Calcineurin phosphatase activity and immunosuppression. A review on the role of calcineurin phosphatase activity and the immunosuppressive effect of cyclosporin A and tacrolimus

Scand. J. Immunol.

Regular Article
Delayed Effect of Grapefruit Juice on Pharmacokinetics and Pharmacodynamics of Tacrolimus in a Living-Donor Liver Transplant Recipient