A Follow-Up Report on Potential Drug Interactions with Clementines Two

European Journal of Pharmaceutical Sciences 133 (2019) 54–58

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European Journal of Pharmaceutical Sciences

journal homepage: www.elsevier.com/locate/ejps

A follow-up report on potential drug interactions with clementines: Two single case experiments show no eﬀect on CYP3A-dependent midazolam T clearance

Nicolas Hohmanna,1, Gerd Mikusa, Walter Emil Haefelia, Vedat Schwengerb, Giuseppe Gattusoc, ⁎ Davide Barrecac, Johanna Weissa, a Department of Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany b Department of Endocrinology, Metabolism and Clinical Chemistry, Section of Nephrology, University of Heidelberg, Im Neuenheimer Feld 162, 69120 Heidelberg, Germany c Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche ed Ambientali, Università di Messina, Viale F. Stagno d'Alcontres 31, 98166 Messina, Italy

ARTICLE INFO ABSTRACT

Keywords: We have previously demonstrated that clementines have in vitro drug interaction potential. To assess the clinical Clementine relevance of clementine-drug interaction, two single case experiments with repetitive phenotyping of CYP3A Citrus clementina activity were conducted. Although an increment of 43% in the estimated midazolam clearance (eCLmet) was CYP3A observed during the ﬁrst experiment in a renal transplant patient on tacrolimus after 4-d consumption of Food-drug interaction clementines (1 kg/d), and an increment of +89% of eCL was observed during chronic consumption of Midazolam met clementine juice in a healthy male volunteer, these changes lie within the range of intra-individual variability. Microdosing Therefore one cannot assure a potential drug interaction due to the clementines, but prescribers should be cautious unless further data emerges. In contrast to the juice used for the in vitro assay comprising several ﬂavonoids, this juice only contained hesperidin and narirutin indicating that the drug interactions potential of clementines might depend on the composition varying from batch to batch.

1. Introduction et al., 2017), interactions with drugs are known, including an increase of the bioavailability of tacrolimus (Liu et al., 2009; Peynaud et al., We have recently characterised the drug interaction potential of 2007). clementine juice in vitro, leading i.a. to both an increase in cytochrome To assess the potential clinical relevance of the in vitro findings, we P450 (CYP) 3A4 expression as well as a reduced CYP3A4 activity due to conducted two single case pilot experiments in the well-controlled en- enzyme inhibition (Theile et al., 2017). The case of a 27-y-old female vironment of a clinical pharmacology trial unit and rechallenged the renal transplant patient with a functional kidney allograft and well- renal transplant patient with clementines a year later while monitoring adjusted immunosuppression prompted us to this investigation, because CYP3A activity, tacrolimus pharmacokinetics, and serum creatinine. To she presented a 2.5-fold increase in tacrolimus concentration in whole substantiate the findings, one of the investigators conducted a self-ex- blood, while consuming large amounts of clementines, thus suggesting periment, by chronically exposing himself to clementine juice and re- a potential food-drug interaction. petitively phenotyping his CYP3A activity. Since the results obtained So far, no clinical drug interaction data have been reported for differed from those obtained in the earlier study, we quantified the clementines or clementine juice. Only for mandarin juice a few reports flavonoids in the clementine juice by liquid chromatography coupled to indicate a lack of interaction with CYP3A4 substrates such as cyclos- tandem mass spectrometry (LC-MS/MS) to clarify whether different porine or midazolam (Sorkhi et al., 2007, 2008; Backman et al., 2000). flavonoid compositions might explain the discrepancies. In contrast, for grapefruit juice containing furanocoumarins like ber- gamottin, which are not present in clementines or mandarins (Theile

⁎ Corresponding author at: University Hospital Heidelberg, Department of Clinical Pharmacology and Pharmacoepidemiology, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. E-mail address: [email protected] (J. Weiss). 1 Current address: National Center for Tumor Diseases, Im Neuenheimer Feld 460, 69,120 Heidelberg, Germany. https://doi.org/10.1016/j.ejps.2019.03.013 Received 13 December 2018; Received in revised form 5 March 2019; Accepted 15 March 2019 Available online 21 March 2019 0928-0987/ © 2019 Elsevier B.V. All rights reserved. N. Hohmann, et al. European Journal of Pharmaceutical Sciences 133 (2019) 54–58

2. Materials and methods intake of the oral solution containing 30 μg of midazolam. The volunteer did not consume clementines or grapefruit for several years before 2.1. Materials the experiment, only sporadically drank orange or lemon juice and refrained from intake of any citrus fruit product 14 d before and during The Iso-Disc P-34, 3 mm diameter PTFE membrane (0.45 μm pore the experiment. He did not take any comedication during or 14 d before size) was obtained from Supelco (Bellefonte, PA, USA). HPLC-grade the trial. acetonitrile and water were supplied by Sigma-Aldrich (St. Louis, MO, USA), dimethylformamide (DMF) by Carlo Erba (Milano, Italy). 2.5. Quantification of flavonoids in the clementine juice Hesperidin, narirutin, didymin, sinensetin, nobiletin and tangeretin were supplied from Extrasynthèse (Genay, France). 6,8-di-C-Glucosyl- Prior to analysis, the juice (10.0 mL) was mixed with DMF (10.0 mL) apigenin was separated from Citrus reticulata × Citrus paradisi (Barreca and the mixture was centrifuged for 5 min at 2300 g. The supernatant et al., 2013), 6,8-di-C-glucosyl-diosmetin (lucenin-2 4′-methyl ether) liquid was then filtered through an Iso-Disc P-34 PTFE membrane and chrysoeriol 7-O-neohesperidoside from Citrus sinensis (Barreca (3 mm diameter, 0.45 μm pore size). LC-MS/MS to quantify flavonoids et al., 2016), and they were used as standards. Midazolam (Dormicum® and furanocoumarins in clementine juice was conducted as described V) was obtained from Roche (Grenzach-Wyhlen, Germany). previously (Theile et al., 2017).

2.2. Human subjects 2.6. CYP3A4 phenotyping

The patient (29 years old kidney-transplanted female) was enrolled Midazolam pharmacokinetics is linear over a 30,000-fold dose after obtaining written informed consent into a study program evalu- range, therefore midazolam microdoses are a safe and suitable method ating CYP3A activity changes in patients exhibiting unusual plasma for repetitive CYP3A phenotyping in volunteers and patients (Halama concentrations of CYP3A substrates (Ethics Committee of the Medical et al., 2013; Hohmann et al., 2015). On each phenotyping day blood Faculty of Heidelberg University, approval #S-588/2012). The healthy was collected in heparinised collecting tubes pre-dose, and 2 h, 2.5 h, volunteer was one of the investigators (NH, healthy male, 32 years old) 3 h, and 4 h after the oral administration of a midazolam microdose. and was enrolled after obtaining written informed consent in the con- The tubes were centrifuged within 5 min of sampling (4 °C, 3600 rpm trol group of the same study. for 10 min) and plasma was then transferred into a fresh tube and stored at −20 °C until further analysis. We used a validated ultra- 2.3. Single case experiment I sensitive UPLC-MS/MS method for the quantiﬁcation of midazolam plasma concentrations, (Burhenne et al., 2012). To reduce the sample In February 2015, one year after the initial observation, we invited burden and time on the ward for the participants, we used a limited the patient in whom we had observed alterations in tacrolimus phar- sampling strategy: The partial area under the concentration-time curve macokinetics (Theile et al., 2017) to participate in a single case ex- between 2 and 4 h post-dose (AUC2–4) was constructed to calculate periment assessing CYP3A activity and tacrolimus whole blood con- estimated metabolic midazolam plasma clearance (eCLmet), a validated centrations before, during, and after consumption of 1 kg clementines in vivo biomarker for CYP3A activity, as described earlier (Katzenmaier

(Citrus clementina, var. clemenules; the same variety and the same et al., 2011). AUC0–4 and AUC0-inf were calculated using Kinetica 5.0 amount she had consumed in 2013) per day for 4 consecutive days (ThermoFisher Scientific, Waltham, MA, USA). (exposure/withdrawal-design). The patient did not consume any clementines since the end of 2013. Forty-eight h after the baseline day, 2.7. Tacrolimus quantification the patient was asked to consume > 1 kg of freshly peeled clementines (purchased in February 2015 from Aldi Süd) during her stay in the Tacrolimus whole blood concentrations were measured in the research center and deliberately throughout the rest of the study. After University Hospital's accredited central lab from samples obtained im- measuring vital signs, pre-dose blood samples for drug and creatinine mediately before the morning dose of tacrolimus and 2 and 4 h after concentrations were drawn. The patient drank an oral midazolam so- drug intake with a validated and DAkkS accredited LC-MS/MS metho- lution (3 μg) at the baseline day (−48 h), after the first clementine dology by using the kit “MassTox Immunosuppressant in Whole Blood – consumption, after 48 h of clementine exposure and 1, 3, 5, and 8 d LC/MS/MS” (Chromsystems Instruments & Chemicals GmbH, after the 4-d citrus exposure. On study days, the midazoloam microdose Gräfeling, Germany), automated sample preparation and measurement was always administered together with her oral co-medication (tacro- on a TQD triple quadrupole mass spectrometer (Waters, Eschborn, limus 2 mg–0mg–2.5 mg, sodium mycophenolate 720 mg–0–720 mg, Germany). nebivolol 5 mg–0–0, 48). All co-medication doses were stable during and 14 d before the single case experiment. Tacrolimus C/D-ratio was 3. Results calculated as follows: C/D-ratio (μg/L * 1/mg) = tacrolimus whole blood trough concentration (μg/L)/daily tacrolimus dose (mg). 3.1. Effect of clementine intake on CYP3A activity and tacrolimus levels in a renal transplant patient 2.4. Single case experiment II

We observed no clinically relevant change of midazolam eCLmet To further investigate the eﬀects of clementine constituents, we during the exposure to clementines (Fig. 1) and 24 h post-dis- produced a clementine juice from one batch of fresh clementines (Citrus continuation of clementines midazolam eCLmet was 1030 mL/min, an clementina, var. clemenules) purchased at the end of January 2016 from increase of 43.0% compared to the baseline of 720 mL/min. Later

Aldi Süd and stored the juice at −20 °C until consumption. In February during the withdrawal phase, midazolam eCLmet ranged between 838 2016 the investigator (NH) drank 500 mL of clementine juice daily over and 890 mL/min. Corresponding observed midazolam AUC0–4 and ex- a period of 14 d. After thawing at room temperature, clementine juice trapolated AUC0-inf are summarised in Table S1. was administered once daily in the morning. CYP3A phenotyping was Tacrolimus whole blood peak concentration (Cmax) slightly in- scheduled for 72 h before juice consumption (baseline), the first day of creased from 11.9 μg/mL to 14.9 μg/L after 2 d of clementine con- juice consumption for direct effects, 7 d and 13 d after juice consump- sumption, concurrently Cmin increased from 5.0 to 6.1 μg/L. Tacrolimus tion for chronic effects, and 15 d after juice consumption (dechallenge). C/D-ratio ranged from 0.89 to 1.36. After withdrawal, tacrolimus Cmax On phenotyping days, the volunteer drank the juice 30 min before the was reduced by 13.5% compared to baseline (a drop from 11.9 to

55 N. Hohmann, et al. European Journal of Pharmaceutical Sciences 133 (2019) 54–58

Fig. 1. Midazolam estimated metabolic clearance

(eCLmet), steady-state tacrolimus whole blood concentrations at trough as well as 2 h and 4 h after oral dosing, and concentration/dose ratio (C/D) during a single case experiment (challenge/withdrawal-design) conducted over 12 d with a 28-year old female renal transplant patient. Over 1 kg of clementines daily was ingested over a course of 4 d (0 h to 96 h).

C/D = 1.11 C/D = 1.11 C/D = 1.36 C/D = 1.07 C/D = 1.07 C/D = 1.00 C/D = 0.89

10.3 μg/L) and later increased to 19.1 μg/L, while the trough con- Table 1 centration was virtually unchanged. Tacrolimus peak whole blood Flavonoid content in the clementine juice consumed by the healthy volunteer concentrations were subject to a greater fluctuation and ranged be- (2016) compared to the juice used for the in vitro experiments (2014) (mg/L). μ tween 6.2 and 19.1 g/L (Fig. 1), independently of clementine intake. Compound Clementine juice Clementine juice (2016) (2014)* 3.2. Effect of clementine juice on CYP3A activity in a healthy volunteer 6,8-di-C-glucosyl-apigenin < 0.1 0.70 ± 0.09 6,8-di-C-glucosyl-diosmetin < 0.1 0.30 ± 0.02 The eCLmet at baseline was 552 mL/min. Over the course of juice Narirutin 6.20 ± 1.50 71.8 ± 3.70 consumption, the eCLmet progressively increased until reaches Chrysoeriol 7-O- < 0.1 0.70 ± 0.03 1045 mL/min (+89%) 24 h after the last juice ingestion (Fig. 2). This neohesperidoside corresponded to a reduction of 44% of the midazolam AUC (Table S2). Hesperidin 42.9 ± 5.40 91.0 ± 6.5 Dydimin < 0.1 2.25 ± 0.32 Sinensetin < 0.1 1.85 ± 0.11 3.3. Effect of clementine intake on the participants' safety parameters Nobiletin < 0.1 1.25 ± 0.17 Tangeretin < 0.1 1.32 ± 0.12 No change of plasma creatinine concentration, heart rate, and blood *Data of the clementine juice from 2014 were published previously (Theile pressure, and no adverse events occurred in the renal transplant patient et al., 2017). and also the healthy volunteer experienced no adverse events. clementine consumption and the in vitro drug interaction potential of 3.4. LC-MS/MS analysis of the clementine juice the compounds present in clementines that may both induce and inhibit drug metabolising enzymes and drug transporters, we conducted two The results of the analysis of the composition of the clementine juice pilot experiments to test the clinical relevance of the in vitro findings, taken by the healthy volunteers are given in Table 1. No fur- which had suggested a possible beverage/food-drug interaction. In fl anocoumarins were detected and the concentrations of most avonoids contrast to the previously observed sharp rise of tacrolimus con- fi detected in the previous study were below the limit of quanti cation. centrations, we were unable to reproduce the effect of clementine ingestion on tacrolimus plasma concentrations in the same patient. The 4. Discussion observed increase in tacrolimus Cmin (5.0 μg/L at −48 h, 6.1 μg/L at +48 h) and Cmax (11.9 μg/L at −48 h, 14.9 μg/L at 48 h) during Based on increased tacrolimus concentrations in a patient under

Fig. 2. Midazolam estimated metabolic clearance (eCLmet) before, during, and after clementine juice ingestion of 500 mL daily for 14 (0 h to 336 h) in a 32-year old male healthy volunteer.

56 N. Hohmann, et al. European Journal of Pharmaceutical Sciences 133 (2019) 54–58 clementine ingestion was within the range of normal intra-patient solely at the intestinal level will only decrease the fraction elimi- ﬂuctuation (Park et al., 2007). The C/D ratio during our single case nated in the gut leaving the hepatic extraction unchanged. experiment ranged between 0.89 and 1.36 (Fig. 1). (3) The mode of administration between in vitro assays and the in vivo

We neither observed changes in midazolam eCLmet indicative of experiment differed. A slower release of constituents upon ingestion significant inhibition of CYP3A4/5 during both experiments, despite of clementines pieces is expected leading to lower local con- the in vitro evidence for CYP3A4/5 inhibition (Theile et al., 2017). The centrations in the intestine. Moreover, fruit skins and the peel observed increase in CYP3A dependent midazolam clearance after contain different constituents (de Castro et al., 2007), which may chronic ingestion of clementines/clementine juice in both participants further contribute to the observed differences. is consistant with induction of CYP3A activity through increased expression of intestinal and/or hepatic CYP3A isozymes. Still the observed Hence, juice for future investigations (e.g. a clinical trial) should be changes of +43% and +89% are also within the known range of intra- analysed for their content of constituents with drug interaction poten- individual variability when repetitively phenotyping a person's CYP3A tial such as tangeretin beforehand. From a clinical perspective, patients activity with midazolam (Halama et al., 2013). treated with narrow therapeutic index CYP3A substrates should be Interestingly, the LC-MS/MS analysis of the juice consumed de- cautious when consuming clementines, because depending on the monstrated that, even though the flavonoid profile was very similar, the constituents high variability of CYP3A substrates levels may occur due concentrations of all components were much lower than in the clem- to enzyme inhibition and possibly enzyme induction. entines the patient consumed in 2013 and which were used for the in vitro experiments in 2014 (Theile et al., 2017): only narirutin and he- 5. Conclusion speridin were present in quantifiable amounts confirming the batch variability as a consequence of harvesting conditions, maturity, ex- Taken together, while ample data and warnings are available for traction techniques, use of degreening agents and to subsequent storage adverse health effects of grapefruit juice in patients on drugs that are conditions (Milella et al., 2011; Fujita et al., 2008; Álvarez et al., 2012) CYP3A substrates, clementines were not under scrutiny, yet. We have (Table 1). Overall, milligram amounts of narirutin (3.1 mg/d) and he- recently provided in vitro evidence for drug interaction potential (Theile speridin (21.0 mg/d) were chronically ingested by the volunteer et al., 2017) and now report in vivo data that clementines or clementine without significant inhibition of CYP3A activity. Up to date, no CYP3A juice do not necessarily lead to relevant inhibition in CYP3A activity. inducing properties have been reported and only very weak inhibition We also provide in vivo data indicative for potential induction of CYP3A of CYP3A4 by hesperidin has been demonstrated (Ho et al., 2001), so activity. Constituents and hence effects on CYP3A-dependent drug that it appears unlikely that the amounts of hesperidin present in our metabolism vary from batch to batch, hence more clinical data such as clementine juice were high enough to provoke CYP3A4 induction or an adequately powered clinical food-drug interaction trial to further clinically relevant CYP3A4 inhibition. While gross changes in enzyme quantify this effect are necessary for a clear recommendation. For now function would have been detected in these single case experiment, the patients taking drugs with a narrow therapeutic index that are CYP3A effects on midazolam clearance (Figs. 1,2) measured upon chronic in- substrates should be cautious when consuming clementines or clem- gestion of clementines/clementine juice albeit consistent with enyzme entine juice. The clinical and analytical data may serve as basis for such induction cannot be distinguished in a definitive manner from ran- a trial. domness in these two cases. Supplementary data to this article can be found online at https:// This is the first clinical evidence demonstrating that clementine doi.org/10.1016/j.ejps.2019.03.013. juice lacking substantial amounts of flavonoids other than narirutin and hesperidin does not inhibit CYP3A substrates. These data also indicate Acknowledgments that the effects observed in vivo and in vitro with the clementine batch from 2013 can most likely be attributed to one or more of the other This research did not receive any specific grant from funding flavonoids like nobiletin, sinensetin, or tangeretin. In addition, these agencies in the public, commercial, or not-for-profit sectors. The au- data underline that different harvesting seasons (November versus thors thank the patient for participating in this study and Monika February), as well as different harvests in general may lead to pro- Wittnebel for excellent technical assistance. foundly different composition of fruits (de Castro et al., 2007). 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