Roles of polymorphic enzymes CYP2D6 and CYP2C19 for in vitro metabolism of amitriptyline at therapeutic and toxic levels

Jornil, Jakob; Línnet, Kristían

doi:10.1007/s11419-008-0063-9

Cited by 7 publications

(5 citation statements)

References 30 publications

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“…Moreover, CYP2C19 or CYP2D6 appears to be the major determinant of Ndemethylation or hydroxylations, respectively. The present results are consistent with previous results showing the involvement of CYP isoforms in AMI metabolism [30][31][32]. In the present study, direct N-glucuronidation of AMI to produce quaternary ammonium glucuronide was observed in only human liver microsomes.…”

Section: Discussionsupporting

confidence: 94%

Determination of species-difference in microsomal metabolism of amitriptyline using a predictive MRM–IDA–EPI method

Lee

et al. 2015

Chemico-Biological Interactions

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Section: Discussionsupporting

confidence: 94%

Determination of species-difference in microsomal metabolism of amitriptyline using a predictive MRM–IDA–EPI method

Lee

et al. 2015

Chemico-Biological Interactions

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“…Dicho protocolo se basa en el cociente de concentraciones metabolito/compuesto original, el consumo concomitante de otras sustancias y la existencia de polimorfismo enzimá-tico. Resulta indispensable, además, tener en cuenta la capacidad metabólica global del individuo y la ingesta concomitante de sustancias que pudieran interaccionar con las enzimas metabolizadoras 36 .…”

Section: Idiosincrasia Del Individuounclassified

Interpretación de resultados toxicológicos post-mórtem: criterios de garantía de calidad

García-Repetto

2015

Revista Española de Medicina Legal

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“…Inhibitor concentrations were 10 M furafylline (inhibitor of CYP1A2), 4 l of CYP2C19 mAb/100 g of HLM protein (inhibitor of CYP2C19), 5 M quinidine (inhibitor of CYP2D6), and 0.5 M ketoconazole (inhibitor of CYP3A4). Inhibitor concentrations were selected based on previous experience (Jornil and Linnet, 2009) and tested to assure adequate inhibition (see below). Inhibition was calculated as the paroxetine-catechol formation rate in the inhibited (v inhibited ) samples (n ϭ 3) relative to the control (v control ) samples (n ϭ 3) (eq.…”

Section: Kinetic Parameters Of Paroxetine Biotransformation By Cp450 mentioning

confidence: 99%

Identification of Cytochrome P450 Isoforms Involved in the Metabolism of Paroxetine and Estimation of Their Importance for Human Paroxetine Metabolism Using a Population-Based Simulator

Jornil¹,

Jensen²,

Larsen³

et al. 2009

Drug Metab Dispos

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ABSTRACT:We identify here for the first time the low-affinity cytochrome P450 (P450) isoforms that metabolize paroxetine, using cDNA-expressed human P450s measuring substrate depletion and paroxetine-catechol (product) formation by liquid chromatography-tandem mass spectrometry. CYP1A2, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 were identified as paroxetine-catechol-forming P450 isoforms, and CYP2C19 and CYP2D6 were identified as metabolizing P450 isoforms by substrate depletion. Michaelis-Menten constants K m and V max were determined by product formation and substrate depletion. Using selective inhibitory studies and a relative activity factor approach for pooled and single-donor human liver microsomes, we confirmed involvement of the identified P450 isoforms for paroxetine-catechol formation at 1 and 20 M paroxetine. In addition, we used the population-based simulator Simcyp to estimate the importance of the identified paroxetine-metabolizing P450 isoforms for human metabolism, taking mechanismbased inhibition into account. The amount of active hepatic CYP2D6 and CYP3A4 (not inactivated by mechanism-based inhibition) was also estimated by Simcyp. For extensive and poor metabolizers of CYP2D6, Simcyp-estimated pharmacokinetic profiles were in good agreement with those reported in published in vivo studies. Considering the kinetic parameters, inhibition results, relative activity factor calculations, and Simcyp simulations, CYP2D6 (high affinity) and CYP3A4 (low affinity) are most likely to be the major contributors to paroxetine metabolism in humans. For some individuals CYP1A2 could be of importance for paroxetine metabolism, whereas the importance of CYP2C19 and CYP3A5 is probably limited.Paroxetine is a selective serotonin reuptake inhibitor used for the treatment of depression, generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, and social anxiety disorder. It is extensively metabolized in humans and exhibits nonlinear kinetics Kaye et al., 1989).After administration of a single dose of paroxetine, poor metabolizers (PMs) and extensive metabolizers (EMs) of CYP2D6 display a 7-fold difference in the median total clearance. Under steady-state (SS) conditions, this difference falls dramatically to 2-fold. Nonlinear paroxetine kinetics is more prominent in EMs of CYP2D6 than in PMs of CYP2D6 (Sindrup et al., 1992a,b). Figure 1 shows the major reported P450 metabolic pathways. CYP2D6 catalyzes demethylation of the methylenedioxy group, presumably yielding paroxetine-catechol and formate (Bloomer et al., 1992). The paroxetine-catechol metabolite is described as an unstable intermediate (Kaye et al., 1989). Catechol-O-methyltransferase enzymes methylate paroxetine-catechol (Maurer et al., 2000), yielding metabolites I and II. In humans, metabolites I and II are found as the conjugated glucuronide or sulfate conjugates in urine, with metabolite I as the main metabolite . CYP2D6 has been identified as a high-affinity paroxetine-metabolizing enzyme, and because PMs...

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Roles of polymorphic enzymes CYP2D6 and CYP2C19 for in vitro metabolism of amitriptyline at therapeutic and toxic levels

Cited by 7 publications

References 30 publications

Determination of species-difference in microsomal metabolism of amitriptyline using a predictive MRM–IDA–EPI method

Determination of species-difference in microsomal metabolism of amitriptyline using a predictive MRM–IDA–EPI method

Interpretación de resultados toxicológicos post-mórtem: criterios de garantía de calidad

Identification of Cytochrome P450 Isoforms Involved in the Metabolism of Paroxetine and Estimation of Their Importance for Human Paroxetine Metabolism Using a Population-Based Simulator

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