Comparison of Cytochrome P450 Mediated Metabolism of Three Central Nervous System Acting Drugs
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The investigation of cytochrome P450 (CYP) mediated metabolism reactions by determination of enzyme kinetic parameters, Michaelis constant (<i>K</i><sub>m</sub>), maximum reaction velocity (<i>V</i><sub>max</sub>), and intrinsic clearance (<i>CL</i><sub>int</sub>) is important aspects in discovery and development of drugs. The kinetic parameters can be used to predict the clearance prior to human administration and for better understanding the mechanism of clearance <i>in vivo</i>. In this study, the metabolic activities of three major hepatic CYP isoforms (2C19, 2D6, and 3A4) were investigated on structurally different central nervous system (CNS) acting drugs, amitriptyline, fluphenazine, and dothiepin. By using our novel <i>in vitro</i> evaluation system, we could compare the kinetic parameters for the metabolism of fluphenazine and dothiepin for the first time. Comparing <i>CL</i><sub>int</sub> values thus obtained, we concluded that 2C19 could be predominant for metabolic activity on tricyclic antidepressants as expected, but not on phenothiazine-related antipsychotic drugs. Since the metabolism of CNS drugs is susceptible to single nucleotide polymorphisms of human gene, our results suggest that phenothiazine could be an alternative to clinical application of CNS drugs.
- Chemical and Pharmaceutical Bulletin
Chemical and Pharmaceutical Bulletin 60(12), 1544-1549, 2012
The Pharmaceutical Society of Japan