title: Cyclosporin toxicity at therapeutic blood levels and cytochrome P-450 IIIA.
abstract: 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.
authors.affiliation: Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109.
authors.forename: M R
authors.initials: MR
authors.lastname: Lucey
authors.forename: J C
authors.initials: JC
authors.lastname: Kolars
authors.forename: R M
authors.initials: RM
authors.lastname: Merion
authors.forename: D A
authors.initials: DA
authors.lastname: Campbell
authors.forename: M
authors.initials: M
authors.lastname: Aldrich
authors.forename: P B
authors.initials: PB
authors.lastname: Watkins
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001944:Breath Tests / Q000379:methods; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D003524:Cyclosporins / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000172:deficiency* / Q000378:metabolism; D004917:Erythromycin; D005069:Evaluation Studies as Topic; D006801:Humans; D015151:Immunoblotting; D007527:Isoenzymes / Q000172:deficiency; D016031:Liver Transplantation; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology; D013268:Stimulation, Chemical; D013997:Time Factors
chemical_list: D002250:Carbon Radioisotopes; D003524:Cyclosporins; D007527:Isoenzymes; D004917:Erythromycin; D003577:Cytochrome P-450 Enzyme System; D012293:Rifampin