Increased tacrolimus blood concentration by Beni‐Madonna – a new hybrid citrus cultivar categorized as ‘Tangor’, in a liver transplant patient: likely furanocoumarin‐mediated inhibition of CYP3A4 or P‐glycoprotein

Abstract

Adverse event

A drug interaction leading to greater exposure to tacrolimus.

Drug implicated

Tacrolimus and Beni‐Madonna (a new cultivar citrus categorized as ‘Tangor’).

The patient

A 9‐month‐old girl with biliary atresia (body weight, 7.5 kg) taking tacrolimus after liver transplantation.

Evidence that links the drug to the event

The time course was consistent with the appearance of the interaction, which was confirmed by an increase in the blood concentration of tacrolimus. Dihydroxybergamottin was detected in peel of Beni‐Madonna and in peel and fruit pulp of grapefruit.

Management

Avoiding Beni‐Madonna intake.

Mechanism

Inhibition of activity of CYP3A4, P‐glycoprotein, or both, by Beni‐Madonna.

Implication for therapy

Clinicians should be aware of this potential interaction, and patients taking drugs such as tacrolimus (the kinetics of which are affected by grapefruit juice) should avoid Beni‐Madonna intake.

Hypothesis to be tested

Further study is required to determine if other Citrus species categorized as Tangor contain furanocoumarins.

In June 2016, a 9‐month‐old girl with biliary atresia (bodyweight, 7.5 kg) underwent liver transplantation (LT). After LT, immunosuppressive medication (http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=6784, http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=7088) was started. The postoperative course was uneventful, and immunosuppressive agents were tapered gradually. She was discharged 35 days after LT, and the immunosuppressive regimen at this point was tacrolimus (0.8 mg, b.i.d.), and methylprednisolone (2.0 mg day⁻¹). The blood concentration of tacrolimus was monitored using a chemiluminescent enzymatic immunoassay. The coefficient of variation (intraday and interday) for the assay was <5%. During 4 months after hospital discharge, the blood concentration of tacrolimus was stable (5–8 ng ml⁻¹). However, in January 2017, the tacrolimus concentration in blood was 16.3 ng ml⁻¹, and she had no subjective symptoms (Figure 1).

Figure 1.

Dose regimen and blood concentration of tacrolimus in our patient. mPSL, methylprednisolone

An interview with her parents revealed that she had taken 150 g of Beni‐Madonna (a type of Citrus species produced in Ehime Prefecture, Japan) before taking tacrolimus after dinner on 2 days before her clinic visit. Her parents confirmed that her adherence to prescribed medicines had been good. There had been no change in medications that could be considered to affect tacrolimus pharmacokinetics. Biochemical variables did not show remarkable abnormalities, with serum creatinine of 0.20 mg dl⁻¹, blood urea nitrogen of 13 mg dl⁻¹, total bilirubin of 0.25 mg dl⁻¹ and aspartate aminotransferase/alanine aminotransferase of 39/33 U l⁻¹ on the same day. Two occasions of tacrolimus intake (the evening on that day and morning of the next day) were discontinued, and the intake restarted with the same dose (0.4 mg, b.i.d.). In the next laboratory test (after 35 days), the tacrolimus concentration had decreased to 6.4 ng ml⁻¹.

Judging from these clinical time courses, we speculated a potential interaction between tacrolimus and Beni‐Madonna. The immunosuppressive drug tacrolimus is metabolized mainly by cytochrome http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=263 and is a substrate of http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=152. The pharmacokinetics of tacrolimus is influenced by several drugs but also by food and beverages, such as grapefruit (Citrus paradisi) juice 1, 2. In particular, furanocoumarins such as bergamottin (BG) and dihydroxybergamottin (DHBG) inhibit the activity of CYP3A4 and P‐gp 3, 4. High performance liquid chromatography (HPLC, referring to the Supporting Information) revealed that the three types of Beni‐Madonna tested contained DHBG in their peels whereas Citrus unshiu did not (Table 1). Therefore, the increase in the tacrolimus concentration in this case might have been due to Beni‐Madonna intake.

Table 1.

Contents of furanocoumarins

	Fruit pulp (segment + juice vesicle)		Peels (flavedo + albedo)
	BG μg ml −1 (μM)	DHBG μg ml −1 (μM)	BG μg ml −1	DHBG μg ml −1
Grapefruit	1.55 (4.57)	3.65 (9.81)	4.54	33.44
Beni‐Madonna I	ND	ND	ND	17.38
Beni‐Madonna II	ND	ND	ND	11.5
Beni‐Madonna III	ND	ND	ND	17.59
Citrus unshiu	ND	ND	ND	ND

albedo, inner peel; BG, bergamottin; DHBG, dihydroxybergamottin; flavedo, outer peel; juice vesicle, membranous content of the fruit endocarp; ND, not detected; segment, innermembrane of the pericarp

Beni‐Madonna is a cultivar bred from hybrid seedlings by crossing Nankou and Amakusa strains. Beni‐Madonna belongs to the Citrus genus and categorized as ‘Tangor’, which is a hybrid of Citrus reticulata and Citrus sinensis. Tangor is different from other popular Citrus species such as oranges (e.g. Valencia and blood) and Citrus fruits (e.g. Citrus unshiu). In addition, HPLC showed different chromatograms between Beni‐Madonna and Citrus unshiu in our study. Therefore, other Citrus species categorized as Tangor also contain DHBG.

An increase in tacrolimus concentration was observed only once in our patient. She showed no remarkable abnormalities in symptoms or laboratory tests, so this increase in tacrolimus concentration did not seem to be of clinical concern. The duration of exposure to elevated tacrolimus may have been insufficient to have a toxic pharmacological effect.

In summary, Beni‐Madonna may increase the blood concentration of tacrolimus by inhibiting activity of CYP3A4 or P‐glycoprotein or both. Patients taking drugs such as tacrolimus, whose kinetics are affected by grapefruit juice, should avoid Beni‐Madonna intake. Further study is required to ascertain if other Citrus species categorized as Tangor contain furanocoumarins.

Nomenclature of targets and ligands

Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guidetophar-macology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 5, and are permanently archived in the Concise Guide to PHARMACOLOGY 2017/18 6, 7.

Competing Interests

There are no competing interests to declare.

We thank Professor Nobuyuki Taniguchi (Division of Clinical Laboratory Medicine, Jichi Medical University), Mr. Yoshiichi Hashimoto and Mr. Katsutoshi Takanami (Department of Clinical Laboratory Medicine, Jichi Medical University Hospital) and Ms. Hisae Shiokawa (Division of Clinical Pharmacology, Jichi Medical University) for carrying out tacrolimus measurements, checking cross‐reactivity with DHBG and providing the data of coefficient of variation. We thank Arshad Makhdum, PhD, from Edanz Group ( www.edanzediting.com/ac ) for editing a draft of this manuscript.

Contributors

K.U., Y.I. and A.F. wrote the manuscript. K.U., K.M., S.O. and A.F. designed the study. K.M., S.O., K.O., Y.S., Y.H., Y.I. and T.U. conducted medical treatment. K.U. and S.O. carried out the research.

Supporting information

Data S1 Supplemental methods

Ushijima, K. , Mizuta, K. , Otomo, S. , Ogaki, K. , Sanada, Y. , Hirata, Y. , Ihara, Y. , Urahashi, T. , Imai, Y. , and Fujimura, A. (2018) Increased tacrolimus blood concentration by Beni‐Madonna – a new hybrid citrus cultivar categorized as ‘Tangor’, in a liver transplant patient: likely furanocoumarin‐mediated inhibition of CYP3A4 or P‐glycoprotein. Br J Clin Pharmacol, 84: 2933–2935. 10.1111/bcp.13743.