Cytochrome P450 3A-mediated metabolism of the topoisomerase I inhibitor 9-aminocamptothecin: Ιmpact on cancer therapy

Maier-Salamon,Alexandra; Thalhammer,Theresia; Reznicek,Gottfried; Böhmdorfer,Michaela; Zupkó,István; Hartl,Alexander; Jaeger,Walter

doi:10.3892/ijo.2014.2473

August-2014 Volume 45 Issue 2

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August-2014 Volume 45 Issue 2

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Article

Cytochrome P450 3A-mediated metabolism of the topoisomerase I inhibitor 9-aminocamptothecin: Ιmpact on cancer therapy

Authors:
- Alexandra Maier-Salamon
- Theresia Thalhammer
- Gottfried Reznicek
- Michaela Böhmdorfer
- István Zupkó
- Alexander Hartl
- Walter Jaeger
View Affiliations / Copyright

Affiliations: Department of Clinical Pharmacy and Diagnostics, University of Vienna, A-1090 Vienna, Austria, Institute of Pathophysiology and Allergy Research, Centrum for Pathophysiology and Infectiology, Medical University of Vienna, A-1090 Vienna, Austria, Department of Pharmacognosy, University of Vienna, A-1090 Vienna, Austria, Department of Pharmacodynamics and Biopharmacy, University of Szeged, Szeged 6720, Hungary
Pages: 877-886
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Published online on: May 29, 2014

https://doi.org/10.3892/ijo.2014.2473
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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 (Vmax/Km) 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.

Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Cytochrome P450 3A-mediated metabolism of the topoisomerase I inhibitor 9-aminocamptothecin: Ιmpact on cancer therapy

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