title: Pharmacokinetic self-potentiation of idarubicin by induction of anthracycline carbonyl reducing enzymes.
abstract: Severe myelosuppression is one of the major adverse effects of Idarubicin (IDA). Especially, after two sequential therapy courses, IDA showed a stronger myelosuppression than after the first course. IDA was metabolized in liver by carbonyl reducing enzymes (CRE) to its 13-OH metabolite, idarubicinol(IDAol),which is more active compared with IDA. RLN-B2, a rat liver cell line, precultured in the presence of IDA showed higher CRE activity compared with non-precultured cells. A crude extract of the enzyme obtained from the livers of F344 rats preadministered IDA 7 days before they were sacrificed showed higher enzymatic activity than that from non-preadministered rats. At 4 h after IDA i.v., the production of IDAol was facilitated in the preadministered group compared with the non-preadministered group. In conclusion, CRE was induced by IDA pretreatment in vitro and vivo, resulting in increased IDAol, which could cause self-potentiation of the myelosuppressive and probably antitumor effects of IDA.
authors.affiliation: First Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan.
authors.forename: Taro
authors.initials: T
authors.lastname: Yamashita
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Fukushima
authors.forename: Takanori
authors.initials: T
authors.lastname: Ueda
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D018943:Anthracyclines; D002460:Cell Line; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015255:Idarubicin / Q000378:metabolism / Q000493:pharmacokinetics*; D008099:Liver / Q000166:cytology / Q000201:enzymology; D010599:Pharmacokinetics; D051381:Rats
chemical_list: D018943:Anthracyclines; D000429:Alcohol Oxidoreductases; D015255:Idarubicin