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.

Keywords:

• Idarubicin
• carbonyl-reducing enzyme
• self-potentiation
• idarubicinol