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

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A Follow-Up Report on Potential Drug Interactions with Clementines Two European Journal of Pharmaceutical Sciences 133 (2019) 54–58 Contents lists available at ScienceDirect 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 volun- teer 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.
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