title: Effect of repeated oral doses of a novel immunosuppressive macrolide lactone on hepatic mixed-function oxidase system in the rat. Comparative study with ciclosporin.
abstract: Effect of pretreatment of rats with FK506((-)-(1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-17-allyl-1,14- dihydroxy-12-[(E)-2-[(1R,3R,4R)-4-hydroxy-3methoxycyclohexyl]-1- methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4- azatricyclo-[22.3.1.0(4.9)]octacos-18-ene-2,3,10,16-tetrone hydrate, CAS 104987-11-3) on microsomal cytochrome P-450 system and oxidations of the administered drug and other model substrates were studied and compared with those of a pharmacologically related drug, ciclosporin (cyclosporin A). Oral treatment of male Sprague-Dawley rats with FK506 (0.4, 2 or 10 mg/kg/d) for 7 days did not decrease microsomal content of total cytochrome P-450 in livers, but rather increased the content in groups with the dose of 0.4 or 10 mg/kg to the levels of 126-130% of the control. Microsomal NADPH-cytochrome c reductase activities were decreased up to 67% of the control with the increasing dose of FK506 and to 62% in a group treated orally with cyclosporin A (25 mg/kg/d for 7 days), although another microsomal electron-transport component, cytochrome b5, was rather increased in all the treated groups. Treatment with FK506 or cyclosporin A did not reduce but slightly increased microsomal activities of aniline hydroxylation, p-nitroanisole O-demethylation and O-ethoxyresorufin O-deethylation. Microsomal depropylation of 7-propoxycoumarin, a typical P-450IIIA-substrate, was also not reduced in all dose groups of FK506, while it was decreased by the treatment with 25 mg/kg cyclosporin A.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmacokinetics and Drug Metabolism, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Iwasaki
authors.forename: T
authors.initials: T
authors.lastname: Shiraga
authors.forename: H
authors.initials: H
authors.lastname: Matsuda
authors.forename: K
authors.initials: K
authors.lastname: Noda
authors.forename: Y
authors.initials: Y
authors.lastname: Yamazoe
authors.forename: K
authors.initials: K
authors.lastname: Nagata
authors.forename: T
authors.initials: T
authors.lastname: Yasumori
authors.forename: S
authors.initials: S
authors.lastname: Ozawa
authors.forename: M
authors.initials: M
authors.lastname: Shimada
authors.forename: N
authors.initials: N
authors.lastname: Murayama
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D016572:Cyclosporine / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008797:Metyrapone / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D009929:Organ Size / Q000187:drug effects; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013050:Spectrometry, Fluorescence; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D007166:Immunosuppressive Agents; D007202:Indicators and Reagents; D011506:Proteins; D016572:Cyclosporine; D006899:Mixed Function Oxygenases; D016559:Tacrolimus; D008797:Metyrapone