Substrates of Human CYP2D6
Shufeng Zhou in Cytochrome P450 2D6, 2018
Paroxetine, an SSRI used for the treatment of depressive disorders (Gunasekara et al. 1998), is mainly inactivated by CYP2D6 via demethylenation of the methylenedioxy group, yielding a catechol metabolite and formic acid (Bloomer et al. 1992). Approximately 64% of a 30-mg oral dose of par-oxetine is excreted in the urine with 62% as metabolites over a 10-day postdosing period. The principal metabolites of paroxetine are polar and conjugates of oxidative and methylated metabolites. Paroxetine is mainly (80%) metabolized by CYP2D6 via demethylenation of the methylenedioxy group, giving rise to an inactive catechol metabolite, which is then either O-methylated or O-glucuronidated, and the by-product formic acid (Figure 3.13) (Bloomer et al. 1992). Saturation and mechanism-based inhibition of CYP2D6 by paroxetine at clinical doses appears to explain for the nonlinear pharmacokinetics of paroxetine with increasing dose and increasing duration of treatment.
Disorders of brain structure and function and crime
John C. Gunn, Pamela J. Taylor in Forensic Psychiatry, 2014
Paroxetine and imipramine are selective serotonin reuptake inhibitors (SSRIs) and antidepressants. Reduced numbers of paroxetine and imipramine binding sites (i.e. binding to the 5-HTT) on platelets, and significant inverse correlations between binding sites and measures of aggression and impulsivity, have been described in children with conduct disorder and ADHD (Stoff et al., 1987; Oades et al., 2002; Stadler et al., 2004), outpatients with episodic aggression (Brown et al., 1989), adolescents with schizophrenia (Modai et al., 1989), patients with personality disorder and a history of self-mutilation (Simeon et al., 1992) and various samples of patients with mixed personality disorders (Cocarro et al., 1995, 1996a,b, 1997a,b). These studies have been almost exclusively conducted with boys or men. There is only one study reported of a sample of women with borderline personality disorder (BPD) (Ng et al., 2005); reduced platelet paroxetine binding was found but 5-HT function did not correlate with self-reported impulsivity.
Generalized Anxiety Disorder
Stephen M. Stahl, Bret A. Moore in Anxiety Disorders: A Guide for Integrating Psychopharmacology and Psychotherapy, 2013
The poor side-effect profile of TCAs, particularly the potential for lethal overdose, limited their use. Subsequently, the SSRI antidepressants were also found effective for GAD, as well as other anxiety disorders. Paroxetine was one of the earliest to be evaluated, in an open comparison with imipramine and 2′-chlord-esmethyldiazepam, and the first SSRI to be approved for the treatment of GAD. As before, all three drugs produced significant improvement, with diazepam initially more efficacious than the two antidepressants, and somatic symptoms showing the best response. But by the 4th week, paroxetine and imipramine were more effective than diazepam, with greater benefit for psychic symptoms (Rocca, Fonzo, Scotta, Zanalda, & Ravizza, 1997). These results were replicated in several double-blind, placebo-controlled studies in outpatients (Pollack et al., 2001; Rickels et al., 2003; Stocchi et al., 2003). Response and remission rates for paroxetine were 62–68& and 30–36&, respectively, with 46& and 20& respectively for the placebo groups. Significantly, more paroxetine than placebo patients reported adverse side effects, notably sexual dysfunction but also asthenia, constipation, and nausea, similar to those occurring during treatment for depression. In a continuation phase, responders were randomly assigned to double-blind treatment with paroxetine or placebo for another 24 weeks. Significantly fewer paroxetine patients relapsed (10.9&) than placebo patients (39.9&) (Sheehan & Mao, 2003; Stocchi et al., 2003).
GRK2 and GRK5 as therapeutic targets and their role in maladaptive and pathological cardiac hypertrophy
Published in Expert Opinion on Therapeutic Targets, 2019
Paroxetine is a selective serotonin reuptake inhibitor (SSRI) class of antidepressants. Paroxetine was found to have selective GRK2 inhibition through disrupting its active site in a way that ATP can no longer bind [77]. Paroxetine was able to prevent GRK2-mediated phosphorylation of light-sensitive rhodopsin at a pIC50 of 4.7 ± 0.04 nM, phosphorylation of tubulin at a pIC50 of 5.6 ± 0.07 nM, and phosphorylation of thyrotropin-releasing hormone receptor at a IC50 of ~30 μM [77]. GRK2’s thermostability was also increased with paroxetine. Early experiments using paroxetine in vitro, showed paroxetine increasing βAR-mediated myocardial contractility after isoproterenol. Currently, paroxetine has not been used in vivo in a pressure-overload maladaptive hypertrophy model. However, it has been used in an MI model of HF where GRK2 is also involved in the pathophysiology [78,79]. Chronic paroxetine treatment (5 mg/kg/day) after 2 weeks post-MI in mice not only improved cardiac function, but limited adverse ventricular remodeling [78]. HW/TL and heart length/TL were significantly blunted at the end of 4 weeks of paroxetine treatment after MI.
Asymmetric organocatalysis in drug discovery and development for active pharmaceutical ingredients
Published in Expert Opinion on Drug Discovery, 2023
(-)-Paroxetine is a selective serotonin reuptake inhibitor that is prescribed for depression and other nervous disorders. In 2019, Kappe and Pericàs reported a multigram-scale flow synthesis of the chiral intermediate 31 of this API starting with the p-fluorocinamaldehyde 29 along with dimethyl malonate 18 and acetic acid using the immobilized Jørgensen-Hayashi diphenylprolinol silyl ether 30 (in a packed bed reactor heated at 60°C) (Figure 4 a) [49]. The reaction was run on the multi-gram scale to produce 17.26 g of intermediate 31 over a 7 h period with a residence time of 20 min and a flow rate of 70 μL/min, with an accumulated TON of 132. This large-scale synthesis had a productivity of 2.47 g/h of pure product, which was considered an outstanding result for organocatalytic reactions under flow conditions. This intermediate was then transformed into an advanced phenylpiperidine 32, which is a key intermediate of (-)-paroxetine, by a tandem reductive amination-lactamization sequence, also conducted under continuous flow conditions.
Developments in the discovery and design of intranasal antidepressants
Published in Expert Opinion on Drug Discovery, 2020
Małgorzata Panek, Paweł Kawalec, Andrzej Pilc, Władysław Lasoń
Paroxetine and buspirone hydrochloride are antidepressants characterized by poor bioavailability during oral administration due to their extensive first-pass metabolism. To improve the nose-to-brain delivery of paroxetine and buspirone hydrochloride, the use of nanoemulsion [92] and microemulsion [93] systems, respectively, was investigated. Paroxetine is a selective serotonin reuptake inhibitor. In clinical practice, it is used in the treatment of depression and anxiety. It was shown that paroxetine-loaded nanoemulsion provides rapid antidepressant effects due to fast paroxetine permeation by high transnasal mucosal flux and quantity effective delivery of paroxetine to the brain [92]. Buspirone hydrochloride belongs to class 3 nonsedating psychotropic drugs and has selective anxiolytic properties. To improve bioavailability and increase drug concentrations in the brain, chitosan aspartate and hydroxypropyl-β-cyclodextrin have been added to the microemulsion. The obtained result showed that the administration of buspirone mucoadhesive microemulsion significantly increased bioavailability and considerably increased drug concentrations in the brain. The authors concluded that intranasal administration of buspirone microemulsion has a potential to reduce the dose and dosing frequency as well as maximize the therapeutic index due to an enhanced rate and extent of drug transport [93].
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