Qualitative Reaction Phenotyping of P450 Isozymes Involved in the Metabolism of Selegiline to Desmethylselegiline and Methamphetamine

摘要

Selegiline, a selective irreversible inhibitor of monoamino oxidase B, is used in combination with levodopa in the treatment of Parkinson's disease. The literature on the cytochrome P450 enzymes (CYPs) involved in its metabolism to desmethylselegiline (DMS) and methamphetamine (MA) is unclear and sometimes conflicting.1,2,3,4 Most of the studies used high concentrations of substrate (25-1000 (mu)M) in in vitro experiments. The aim of this study is the in vitro characterization of the human CYPs involved in the formation of DMS and MA in human liver microsomes at more therapeutically relevant concentrations of selegiline (1-2 (mu)M) using high-performance liquid chromatography with tandem mass spectrometry. Four approaches for P450 phenotyping reaction were used: c-DNA-expressed human cytochrome P450 enzymes, chemical inhibition, inhibitory antibodies and correlation analysis.