PT  - JOURNAL ARTICLE
AU  - Sébastien J. Provencher
AU  - Christian Demers
AU  - Marie-Claude Bastien
AU  - Jean-Pierre Villeneuve
AU  - Marielle Gascon-Barré
TI  - Effect of Cyclosporine A on Cytochrome P-450-Mediated Drug Metabolism in the Partially Hepatectomized Rat
DP  - 1999 Apr 01
TA  - Drug Metabolism and Disposition
PG  - 449--455
VI  - 27
IP  - 4
4099  - http://dmd.aspetjournals.org/content/27/4/449.short
4100  - http://dmd.aspetjournals.org/content/27/4/449.full
SO  - Drug Metab Dispos1999 Apr 01; 27
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics