title: Effects of clarithromycin and its metabolites on the mixed function oxidase system in hepatic microsomes of rats.
abstract: Clarithromycin and its metabolites have been examined for their abilities to induce specific form(s) of cytochrome P-450 and metabolite complex formation in rats. Pretreatment of rats with clarithromycin,N-demethyl clarithromycin, clarithromycin N-oxide, and decladinosyl clarithromycin resulted in 48-75% decreases in the amount of 2C11 and 100-600% increases in the amount of 3A1. Clarithromycin and N-demethyl clarithromycin, but not decladinosyl clarithromycin, produced a metabolite complex with cytochrome P-450 in vivo. Activities of testosterone 2 beta- and 6 beta-hydroxylases were increased by administration of clarithromycin and N-demethyl clarithromycin when these activities were measured in the presence of ferricyanide, but not significant induction was observed when measured in the absence of ferricyanide. Clarithromycin N-oxide treatment resulted in the increase in hydroxylation of testosterone not only at the 2 beta- and 6 beta-positions (430 and 190%, respectively), but also at 7 alpha-position (60%), regardless of the presence or absence of ferricyanide. In vitro experiments with hepatic microsomes of dexamethasone-pretreated rats indicated that the metabolites that were modified at the tertiary amino group more efficiently produced the metabolite complex with cytochrome P-450 compared with the parent compound. In contrast, decladinosyl and hydroxylated metabolites had similar or lower capacities for metabolite complex formation than did the parent compound. Clarithromycin and its N-modified metabolites were able to induce 3A1 and form a metabolite complex with cytochrome P-450 in vivo in varying extents. Decladinosyl clarithromycin has a weak inducibility of 3A1 and did not form a metabolite complex with cytochrome P-450 in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Laboratory of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Chiba University, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Ohmori
authors.forename: I
authors.initials: I
authors.lastname: Ishii
authors.forename: S
authors.initials: S
authors.lastname: Kuriya
authors.forename: T
authors.initials: T
authors.lastname: Taniguchi
authors.forename: T
authors.initials: T
authors.lastname: Rikihisa
authors.forename: S
authors.initials: S
authors.lastname: Hirose
authors.forename: Y
authors.initials: Y
authors.lastname: Kanakubo
authors.forename: M
authors.initials: M
authors.lastname: Kitada
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D017291:Clarithromycin / Q000378:metabolism / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D005292:Ferricyanides / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D006899:Mixed Function Oxygenases / Q000096:biosynthesis / Q000378:metabolism*; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013250:Steroid Hydroxylases / Q000378:metabolism
chemical_list: D005292:Ferricyanides; C007931:hexacyanoferrate III; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; C022724:testosterone 7-alpha-hydroxylase, hamster; D010089:Oxidoreductases, N-Demethylating; D017291:Clarithromycin