Effect of cyclosporine A on cytochrome P-450-mediated drug metabolism in the partially hepatectomized rat.
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 of 14CO2 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.
Provencher
S J
SJ
Centre de recherche, Centre hospitalier de l'Université de Montréal, Campus Saint-Luc, Montréal, Québec, Canada.
Demers
C
C
Bastien
M C
MC
Villeneuve
J P
JP
Gascon-Barré
M
M
D000632:Aminopyrine / Q000493:pharmacokinetics; D000818:Animals; D001711:Biotransformation; D015152:Blotting, Northern; D002110:Caffeine / Q000493:pharmacokinetics; D002250:Carbon Radioisotopes; D016572:Cyclosporine / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D004917:Erythromycin / Q000493:pharmacokinetics; D006498:Hepatectomy; D007527:Isoenzymes / Q000378:metabolism; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013379:Substrate Specificity
D002250:Carbon Radioisotopes; D007527:Isoenzymes; D012333:RNA, Messenger; D000632:Aminopyrine; D002110:Caffeine; D004917:Erythromycin; D016572:Cyclosporine; D003577:Cytochrome P-450 Enzyme System