RT Journal Article
SR Electronic
T1 Effect of Cyclosporine A on Cytochrome P-450-Mediated Drug Metabolism in the Partially Hepatectomized Rat
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 449
OP 455
VO 27
IS 4
A1 Sébastien J. Provencher
A1 Christian Demers
A1 Marie-Claude Bastien
A1 Jean-Pierre Villeneuve
A1 Marielle Gascon-Barré
YR 1999
UL http://dmd.aspetjournals.org/content/27/4/449.abstract
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