Inhibition of hepatic microsomal drug metabolism by the immunosuppressive agent cyclosporin A

Shabbir M. Moochhala, Kenneth W. Renton

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31 Citations (Scopus)

Résumé

Cyclosporin A (CsA), an orally active immunosuppressive agent, was shown to inhibit cytochrome P-450 dependent biotransformation of drugs in the mouse. It competitively inhibited the hydroxylation of benzo[a]pyrene and the N-demethylation of aminopyrine in hepatic microsomes with Ki values of 93 and 1540 μM respectively. This selective inhibition for benzo[a]pyrene hydroxylase by CsA was substantiated in vivo by selective inhibition of total body clearance of theophylline, but not of antipyrine. CsA was itself N-demethylated by hepatic microsomes with a Km of 808 μM. CsA interacted directly with cytochrome P-450, causing a reverse type I spectral change in hepatic microsomes. No metabolic intermediate complexes could be demonstrated. These results suggest that CsA has the potential to cause drug interactions involving inhibition of drug biotransformation, particularly of drugs that are metabolised by the same types of cytochrome P-450 which oxidise benzo[a]pyrene and theophylline.

Langue d'origineEnglish
Pages (de-à)1499-1503
Nombre de pages5
JournalBiochemical Pharmacology
Volume35
Numéro de publication9
DOI
Statut de publicationPublished - mai 1 1986

Note bibliographique

Funding Information:
* This work was supported by a grant from the Medical Research Council of Canada. t Author to whom all correspondence should be addressed.

ASJC Scopus Subject Areas

  • Biochemistry
  • Pharmacology

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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