Acute intoxication of cyclosporin caused by coadministration of decoctions of the fruits of Citrus aurantium and the pericarps of Citrus grandis

In order to investigate the effects of Citrus herbs on cyclosporin absorption and disposition, swine were given cyclosporin (10 mg/kg) with or without decoctions of Citri Aurantii Fructus (CAF) or Citri Grandis Pericarpium (CGP) in a crossover design. FPIA method (fluorescence polarization immunoassay) was used to determine the blood concentration of cyclosporin. The decoctions were characterized by their flavanone contents. Our results indicated that the coadministration of CAF and CGP significantly increased the C(max) of cyclosporin by 64% and 79%, respectively. The AUC of cyclosporin was significantly elevated by 97% when coadministered with CGP. Among the swine, 1/5 and 3/5 exhibited acute toxicity of cyclosporin after concomitant intake of CAF and CGP, respectively. This indicates an interaction of Citrus compounds with a commonly used drug. We suggest when cyclosporin is coadministered with these Citrus decoctions, the blood concentration of cyclosporin should be carefully monitored for close adjustment to avoid cyclosporin intoxication.