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COMPARATIVE STUDIES ON THE CYTOCHROME P450-ASSOCIATED METABOLISM AND INTERACTION POTENTIAL OF SELEGILINE BETWEEN HUMAN LIVER-DERIVED IN VITRO SYSTEMS

Orion Pharma, Preclinical and Clinical R&D, Turku, Finland (J.S.S., L.N.); Imperial College, Division of Medicine, Section on Clinical Pharmacology, London, United Kingdom (A.R.B., R.J.E., P.W.); BIBRA International Ltd., Carshalton, Surrey, United Kingdom (B.G.L., R.J.P., A.B.R.); Unidad Hepatología Experimental, Centro de Investigación, Hospital Universitario La Fe, Valencia, Spain (M.-J.G.-L., J.V.C.); Karolinska Institutet, Institute of Environmental Medicine, Division of Molecular Toxicology, Stockholm, Sweden (M.I.-S., M.H.); University of Rennes, Faculty of Pharmacy, INSERM U456, Rennes, France (A.G., L.C.); University of Surrey School of Biological Sciences, Guildford, Surrey, United Kingdom (P.S.G., D.F.V.L.); and University of Oulu, Department of Pharmacology and Toxicology, Oulu, Finland (P.T., O.P.)

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.

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