Comparative studies on the cytochrome p450-associated metabolism and interaction potential of selegiline between human liver-derived in vitro systems. Drug Metab Dispos 2003 Sep;31(9):1093-102
Date
08/16/2003Pubmed ID
12920164DOI
10.1124/dmd.31.9.1093Scopus ID
2-s2.0-10744227166 (requires institutional sign-in at Scopus site) 76 CitationsAbstract
Selegiline was used as a model compound in a project aimed at comparing, evaluating, and integrating different in vitro approaches for the prediction of cytochrome p450 (p450)-catalyzed hepatic drug metabolism in humans (EUROCYP). Metabolic predictions were generated using homology modeling, cDNA-expressed p450 enzymes, human liver microsomes, primary cultured human hepatocytes, and precision-cut human liver slices. All of the in vitro systems correctly indicated the formation of two dealkylated metabolites, desmethylselegiline and methamphetamine. The metabolic instability of selegiline was demonstrated by all of the in vitro systems studied. Estimates of clearance varied from 16 l/h to 223 l/h. With the exception of one approach, all systems underpredicted the in vivo clearance in humans (236 l/h). Despite this, all approaches successfully classified selegiline as a high clearance compound. Homology modeling suggested the participation of CYP2B6 in the demethylation of selegiline and of CYP2D6 in the depropargylation of the drug. Studies with recombinant expressed enzymes and with human hepatic microsomal fraction supported the involvement of CYP2B6 but not of CYP2D6. These techniques also suggested the involvement of CYP1A2, CYP2C8, and CYP2C19 in the biotransformation of selegiline. In vitro, CYP2B6 was the most active form of p450 involved in selegiline metabolism. Metabolism by several enzymes operating in parallel implies a low interaction potential for the drug. None of the techniques alone was able to predict all aspects of the metabolic and kinetic behavior of selegiline in vivo. However, when used as an integrated package, all significant characteristics were predictable.
Author List
Salonen JS, Nyman L, Boobis AR, Edwards RJ, Watts P, Lake BG, Price RJ, Renwick AB, Gómez-Lechón MJ, Castell JV, Ingelman-Sundberg M, Hidestrand M, Guillouzo A, Corcos L, Goldfarb PS, Lewis DF, Taavitsainen P, Pelkonen OMESH terms used to index this publication - Major topics in bold
Cells, CulturedCytochrome P-450 Enzyme System
Drug Interactions
Enzyme Inhibitors
Hepatocytes
Humans
In Vitro Techniques
Isoenzymes
Microsomes, Liver
Models, Molecular
Recombinant Proteins
Selegiline
