Comparison of Cytochrome P450 Mediated Metabolism of Three Central Nervous System Acting Drugs

Abstract

The investigation of cytochrome P450 (CYP) mediated metabolism reactions by determination of enzyme kinetic parameters, Michaelis constant (K m ), maximum reaction velocity (V max ), and intrinsic clearance (CL int ) 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 in vivo. 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 in vitro evaluation system, we could compare the kinetic parameters for the metabolism of fluphenazine and dothiepin for the first time. Comparing CL int 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.

Non-additivity of the functional properties of individual P450 species and its manifestation in the effects of alcohol consumption on the metabolism of ketamine and amitriptyline

“…Although our results are consistent with the earlier studies pointing out CYP3A4, CYP2B6, and CYP2C9 as the major metabolizers of ketamine [35-37] and CYP3A4, CYP2C19, and CYP2D6 as the most efficient catalysts of amitriptyline demethylation [38, 40-41], we revealed some other, yet unidentified, important players in the metabolism of these substrates. Thus, surprisingly, CYP4A11 was identified as the most efficient metabolizer of ketamine.…”

“…Notably, the turnover rates for amitriptyline demethylation observed in our experiments (19 - 60 min -1 , Table 2) are considerably higher than those reported in the literature (1.5 - 15 min -1 [38, 40-41]). This apparent discrepancy is likely caused by a difference in the methods of detecting the demethylation products.…”

“…In the case of amitriptyline, the most efficient metabolizers are CYP2D6, CYP2C19, CYP2A6, and CYP3A4 (Table 2). According to our results, in terms of catalytic efficiency CYP2D6 outperforms CYP2C19, which was assumed the most potent metabolizer of amitriptyline in the earlier studies [38, 40]. New in this list is CYP2A6, which has not been yet probed on its ability to metabolize amitriptyline.…”

“…Although the role of the individual P450 enzymes in the demethylation of ketamine [34-37] and amitriptyline [38-41] has been already addressed in the literature, our knowledge of the catalytic parameters of drug-metabolizing P450 species with these substrates remains essentially incomplete. In this study, we used our high-throughput technique to examine the kinetics of P450-catalyzed demethylation reactions [30] to characterize the ability of eleven human cytochrome P450 species (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4, 3A5, and 4A11) to metabolize ketamine and amitriptyline.…”

Tools for optimising pharmacotherapy in psychiatry (therapeutic drug monitoring, molecular brain imaging and pharmacogenetic tests): focus on antidepressants

“…The major enzyme involved in dothiepin metabolism is CYP2C19 (Attia et al 2012) and to a lesser extent CYP2D6 (Yu DK et al 1986). Although CYP2C19 wild-type (WT) had high metabolic activity for dothiepin metabolism, the E72K mutation of CYP2C19 (Glu72!Lys72) decreases enzymatic activity by 29-37%, while binding affinities were diminished 2.5to 20-fold (Attia et al 2012;Attia et al 2014). On the other hand, low activity and low affinity of CYP2C9 WT is recovered notably by a K72E mutation (Attia et al 2014).…”