title: Cytochrome P450 3A-mediated metabolism of the topoisomerase I inhibitor 9-aminocamptothecin: impact on cancer therapy.
abstract: The metabolism of 9-aminocamptothecin (9-AC) was investigated in human and rat liver microsomes. In both species 9-AC was almost exclusively biotransformed to dihydroxy-9-AC (M1) and monohydroxy-9-AC (M2). The enzymatic efficiencies of the formation of M1 and M2 (V(max)/K(m)) were 1.7- and 2.7‑fold higher in rat than in human liver microsomes indicating species-related differences in 9-AC hydroxylation. Incubation in the presence of human recombinant cytochrome P450 (CYP) enzymes demonstrated that the formation of M1 and M2 is mainly catalyzed by CYP3A4 and only to a minor extent by extrahepatic CYP1A1. The predominant role of CYP3A4 was further supported by a dramatic inhibition of metabolite formation in the presence of the CYP3A4 substrates troleandomycin and ketoconazole. Experiments conducted in isolated perfused rat livers further demonstrated that biliary excretion of 9-AC, M1 and M2 during 60 min of perfusion was pronounced and accounted for 17.7±2.59, 0.05±0.01 and 2.75±0.14% of total 9-AC applied to the liver, respectively. In summary, this study established that CYP3A-dependent hydroxylation is the main metabolic pathway for 9-AC in rat and human liver, which have to be taken into consideration during cancer therapy of patients.
authors.affiliation: Department of Clinical Pharmacy and Diagnostics, University of Vienna, A-1090 Vienna, Austria.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Maier-Salamon
authors.affiliation: Institute of Pathophysiology and Allergy Research, Centrum for Pathophysiology and Infectiology, Medical University of Vienna, A-1090 Vienna, Austria.
authors.forename: Theresia
authors.initials: T
authors.lastname: Thalhammer
authors.affiliation: Department of Pharmacognosy, University of Vienna, A-1090 Vienna, Austria.
authors.forename: Gottfried
authors.initials: G
authors.lastname: Reznicek
authors.affiliation: Department of Clinical Pharmacy and Diagnostics, University of Vienna, A-1090 Vienna, Austria.
authors.forename: Michaela
authors.initials: M
authors.lastname: Böhmdorfer
authors.affiliation: Department of Pharmacodynamics and Biopharmacy, University of Szeged, Szeged 6720, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Zupkó
authors.affiliation: Department of Clinical Pharmacy and Diagnostics, University of Vienna, A-1090 Vienna, Austria.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hartl
authors.affiliation: Department of Clinical Pharmacy and Diagnostics, University of Vienna, A-1090 Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Jaeger
mesh_terms: D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D059004:Topoisomerase I Inhibitors / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D059004:Topoisomerase I Inhibitors; C080125:9-aminocamptothecin; D051544:Cytochrome P-450 CYP3A; D002166:Camptothecin