RT Journal Article
SR Electronic
T1 Cyclosporine metabolism by rat liver microsomes. Evidence for involvement of enzyme(s) other than cytochromes P-450 3A.
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 730
OP 737
VO 21
IS 4
A1 T Prueksaritanont
A1 M A Correia
A1 A E Rettie
A1 D C Swinney
A1 P E Thomas
A1 L Z Benet
YR 1993
UL http://dmd.aspetjournals.org/content/21/4/730.abstract
AB Cyclosporine (CyA) metabolism was investigated in liver microsomes obtained from untreated male and female Sprague-Dawley rats, and rats pretreated with ethinyl estradiol (EE), dexamethasone (DX), and phenobarbital (PB). Total hepatic microsomal cytochrome P-450 content of DX- and PB-treated male and female rats was significantly higher than that of their respective control or EE-treated rats. However, CyA metabolism was significantly increased, by all drug pretreatments, both in male and female rats. EE increased (2-5 fold) the formation of AM9 (a hydroxylated metabolite) and AM1c (a cyclized-hydroxylated product) over the CyA concentration range tested (0.2-42 microM). DX and PB significantly increased (2- to 20-fold) all detected metabolites (AM1, another hydroxylated metabolite; AM9; AM4N, an N-demethylated product; and AM1c), especially at high substrate concentrations (above 1.25 microM). Immunoblot analyses revealed that the microsomal P-450 3A2 content was decreased in EE-treated male rats, but markedly induced in those treated with either DX or PB. P-450 3A1 was undetectable in untreated and EE-treated female rats, but greatly induced in DX-treated male and female rats. Examination of P-450 3A activity, using 6 beta-hydroxytestosterone formation as a probe, confirmed the immunoblot results. These studies suggest that enzyme(s), other than P-450s 3A1 and 3A2 also play a significant role in CyA metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)