Cyclosporin toxicity at therapeutic blood levels and cytochrome P-450 IIIA

Lancet. 1990 Jan 6;335(8680):11-5. doi: 10.1016/0140-6736(90)90137-t.


A 40-year-old male liver allograft recipient had neurological dysfunction and renal failure while his cyclosporin blood levels were in the therapeutic range; these features recurred on rechallenge. The hypothesis that this toxic effect might have resulted from abnormal metabolism of cyclosporin by liver cytochrome P-450 IIIA was investigated with the [14C]erythromycin breath test, which is a measure of this enzyme's activity. P-450 IIIA activity was decreased compared with that in controls, including other liver transplant recipients. Pretreatment with rifampicin, an inducer of P-450 IIIA, increased enzyme activity. After treatment with rifampicin the patient could be rechallenged with cyclosporin at a dose almost twice that which had previously been toxic. The patient died during a second transplantation and the microsomal content of P-450 IIIA was found to be low in the first transplant.

Publication types

  • Case Reports
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Administration, Oral
  • Adult
  • Breath Tests / methods
  • Carbon Radioisotopes
  • Chromatography, High Pressure Liquid
  • Cyclosporins / administration & dosage
  • Cyclosporins / adverse effects*
  • Cyclosporins / blood
  • Cyclosporins / metabolism
  • Cytochrome P-450 Enzyme System / deficiency*
  • Cytochrome P-450 Enzyme System / metabolism
  • Erythromycin
  • Evaluation Studies as Topic
  • Humans
  • Immunoblotting
  • Isoenzymes / deficiency
  • Liver Transplantation*
  • Male
  • Microsomes, Liver / enzymology
  • Rifampin / administration & dosage
  • Rifampin / pharmacology
  • Stimulation, Chemical
  • Time Factors


  • Carbon Radioisotopes
  • Cyclosporins
  • Isoenzymes
  • Erythromycin
  • Cytochrome P-450 Enzyme System
  • Rifampin