Structural Characterization of Novel Adenine Dinucleotide Phosphate Conjugates of Imatinib in Incubations with Rat and Human Liver Microsomes
| Autor: | Magang Shou, Shuguang Ma, Michael L. Schrag, Yang Xu, Raju Subramanian |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Magnetic Resonance Spectroscopy
medicine.drug_class Metabolite Pharmaceutical Science Mass Spectrometry Piperazines Tyrosine-kinase inhibitor Cofactor chemistry.chemical_compound NAD+ Nucleosidase hemic and lymphatic diseases medicine Animals Humans Protein Kinase Inhibitors Chromatography High Pressure Liquid Pharmacology Molecular Structure biology Chemistry Imatinib Rats B vitamins Pyrimidines Imatinib mesylate Biochemistry Enzyme inhibitor Benzamides Imatinib Mesylate Microsomes Liver biology.protein Microsome NADP medicine.drug |
| Zdroj: | Drug Metabolism and Disposition. 36:2414-2418 |
| ISSN: | 1521-009X 0090-9556 |
| DOI: | 10.1124/dmd.108.023085 |
| Popis: | Imatinib, a potent and selective protein tyrosine kinase inhibitor, has been approved for the treatment of chronic myelogenous leukemia and metastatic and unresectable malignant gastrointestinal stromal tumors. In vitro metabolism of imatinib was investigated in rat and human liver microsomes. Besides several oxidative metabolites and an N-desmethyl metabolite, as previous reported, a novel metabolite with a mass addition of 621 atomic mass units to the parent was detected as the major metabolite in the incubations with rat liver microsomes, using NADPH as a cofactor. The analysis of MS(2) and MS(n) data revealed that this metabolite corresponded to adenine dinucleotide phosphate (ADP+) conjugate of imatinib. The ADP+ adduct was scaled up from rat liver microsomal incubations and isolated for NMR analysis. NMR data confirmed and conclusively showed the conjugation had occurred between the pyridine nitrogen of imatinib to the ribose ring of ADP+ moiety. The formation of this adduct was enzymatic and required NADP+ as a reactant. In addition, ADP+ adducts of imatinib N-oxide and desmethyl imatinib were also detected as minor metabolites in the incubations with rat liver microsomes. In contrast, only trace levels of ADP+ adducts of imatinib and desmethyl imatinib were detected in the incubations with human liver microsomes. Imatinib-ADP+ adducts have been observed only in in vitro studies to date. The physiological role of these adducts is not clear, nor is their in vivo relevance. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|