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

We have previously demonstrated that clementines have in vitro drug interaction potential. To assess the clinical relevance of clementine-drug interaction, two single case experiments with repetitive phenotyping of CYP3A activity were conducted. Although an increment of 43% in the estimated midazolam clearance (eCLmet) was observed during the first experiment in a renal transplant patient on tacrolimus after 4-d consumption of clementines (1 kg/d), and an increment of +89% of eCLmet was observed during chronic consumption of clementine juice in a healthy male volunteer, these changes lie within the range of intra-individual variability. 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.