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Research ArticleArticle

Effect of Cyclosporine A on Cytochrome P-450-Mediated Drug Metabolism in the Partially Hepatectomized Rat

Sébastien J. Provencher, Christian Demers, Marie-Claude Bastien, Jean-Pierre Villeneuve and Marielle Gascon-Barré
Drug Metabolism and Disposition April 1999, 27 (4) 449-455;
Sébastien J. Provencher
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Christian Demers
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Marie-Claude Bastien
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Jean-Pierre Villeneuve
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Marielle Gascon-Barré
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Abstract

Despite its hepatotoxic potential, cyclosporine A (CsA) has been reported to positively influence compensatory liver growth. To probe the physiological consequences of CsA on the recovery of liver function, studies were initiated in the 2/3 partially hepatectomized (PHx) rat, taking the recovery of cytochromes P-450-dependent drug metabolism as primary outcome. CsA was administered at a dose of 3.33 mg/kg/day for 10 days. Drug metabolism was evaluated by the recovery of14CO2 after administration of isotopically labeled model drugs and by studying the expression of the P-450 transcripts involved in their biotransformation before and 24 to 96 h after PHx. Before PHx, neither the steady-state mRNA nor the in vivo disposition of caffeine (CYP1A2), erythromycin (CYP3A2 and 3A1), or aminopyrine (CYP2B1 and 2C11) were influenced by CsA. Studies 24 h after PHx revealed a 29 to 39% reduction in the elimination of [14C]aminopyrine and [14C]erythromycin, which was unaffected by CsA. Their metabolism at 48 to 96 h after PHx also remained unaffected by CsA. By contrast, postPHx, [14C]caffeine elimination decreased to a level closely proportional to the loss in liver mass. In addition, CsA accelerated the recovery and/or prevented the decrease of caffeine elimination 24 h after PHx but not at later time points, indicating an early, but unsustained, beneficial effect of CsA on the recovery of CYP1A2-mediated activities. These data show that at the critical time of greatest loss in liver mass, CsA has only a selective influence on the biotransformation of cytochrome P-450 protein-dependent activities and that its effect on the regeneration process does not translate into an overall accelerated recovery of the hepatic drug-metabolizing function.

Footnotes

  • Send reprint requests to: Dr. Marielle Gascon-Barré, Ph.D., M.B.A., Centre de recherche, Campus Saint-Luc, Centre Hospitalier de l’Université de Montréal, 264 René-Lévesque Blvd. East, Montréal (Québec) Canada H2X 1P1. E-mail: gasconbm{at}ere.umontreal.ca

  • These studies were supported by the Medical Research Council of Canada (Grant No. MT-6511). S.P. is the recipient of a Studentship award from the Canadian Liver Foundation.

  • Abbreviations used are::
    CsA
    cyclosporine A
    3-MC
    3-methylcholanthrene
    ALT
    alanine aminotransferase
    βNF
    β-naphthoflavone
    CYP
    cytochrome P-450 gene
    CYP
    cytochrome P-450 protein
    DEX
    dexamethasone
    PB
    phenobarbital
    PHs
    sham-operated animals
    PHx
    2/3 partial hepatectomy/hepatectomized
    • Received June 12, 1998.
    • Accepted January 11, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 27 (4)
Drug Metabolism and Disposition
Vol. 27, Issue 4
1 Apr 1999
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Research ArticleArticle

Effect of Cyclosporine A on Cytochrome P-450-Mediated Drug Metabolism in the Partially Hepatectomized Rat

Sébastien J. Provencher, Christian Demers, Marie-Claude Bastien, Jean-Pierre Villeneuve and Marielle Gascon-Barré
Drug Metabolism and Disposition April 1, 1999, 27 (4) 449-455;

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Research ArticleArticle

Effect of Cyclosporine A on Cytochrome P-450-Mediated Drug Metabolism in the Partially Hepatectomized Rat

Sébastien J. Provencher, Christian Demers, Marie-Claude Bastien, Jean-Pierre Villeneuve and Marielle Gascon-Barré
Drug Metabolism and Disposition April 1, 1999, 27 (4) 449-455;
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