Steady-State Pharmacokinetic, Safety, and Tolerability Profiles of Quetiapine, Norquetiapine, and Other Quetiapine Metabolites in Pediatric and Adult Patients with Psychotic Disorders

Winter, Helen; Earley, Willie; Hamer-Maansson, Jennifer E.; Davis, Patty; Smith, Mark A.

doi:10.1089/cap.2007.0084

Cited by 68 publications

(38 citation statements)

References 26 publications

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“…For example, active metabolites of clozapine (Burstein et al, 2005) and quetiapine (Jensen et al, 2008;Winter et al, 2008) have been reported to have unique profiles differing from that of their mother compounds. A recent report showed that a metabolite of quetiapine (N-desalkylquetiapine) is capable of inhibiting norepinephrine uptake, suggesting that the antidepressant effect of quetiapine in bipolar depression is at least partially mediated by the potent antidepressant activity of N-desalkylquetiapine (Jensen et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Norzotepine, a Major Metabolite of Zotepine, Exerts Atypical Antipsychotic-Like and Antidepressant-Like Actions through Its Potent Inhibition of Norepinephrine Reuptake

Shobo

Yamada²,

Mihara³

et al. 2010

J Pharmacol Exp Ther

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The antipsychotic drug zotepine [ZTP;f]thiepin-10-yl)oxy]-N,N-dimethylethan-1-amine] is known to have not only atypical antipsychotic effects but also antidepressive effects in schizophrenia patients. Norzotepine [norZTP;f]thiepin-10-yl)oxy]-N-methylethan-1-amine] has been postulated to be a major metabolite of ZTP in humans. Here, we characterized norZTP through several in vitro studies and in animal models of psychosis, depression, and extrapyramidal symptoms (EPS) and compared the pharmacological profiles with those of ZTP. Although both compounds showed similar overall neurotransmitter receptor binding profiles, norZTP showed 7-to 16-fold more potent norepinephrine reuptake inhibition than ZTP. In a pharmacokinetic study, both ZTP and norZTP showed good brain permeability when administered individually in mice, although norZTP was not detected in either plasma or brain after intraperitoneal injection of ZTP. In the methamphetamineinduced hyperlocomotion test in mice, norZTP and ZTP showed similar antipsychotic-like effects at doses above 1 mg/kg i.p. In contrast, unlike ZTP, norZTP did not induce catalepsy up to 10 mg/kg i.p. norZTP significantly antagonized the hypothermia induced by reserpine [(3␤,16␤,17␣,18␤,20␣)-11,17-dimethoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]yohimban-16-carboxylic acid methyl ester], suggesting in vivo inhibition of the norepinephrine transporter. In the forced-swim test, norZTP exerted an antidepressant-like effect at the effective doses for its antipsychotic action, whereas ZTP neither antagonized reserpine-induced hypothermia nor showed antidepressant-like effect. These results collectively demonstrate that norZTP exerts more potent inhibitory action than ZTP on norepinephrine transporters both in vitro and in vivo, presumably accounting for its antidepressant-like effect and low EPS propensity. Given that norZTP is the major metabolite observed in humans, norZTP may contribute to the unique clinical profiles of its mother compound, ZTP.

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Section: Discussionmentioning

confidence: 99%

Norzotepine, a Major Metabolite of Zotepine, Exerts Atypical Antipsychotic-Like and Antidepressant-Like Actions through Its Potent Inhibition of Norepinephrine Reuptake

Shobo

Yamada²,

Mihara³

et al. 2010

J Pharmacol Exp Ther

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“…Unfortunately, we have been unable to measure this metabolite. According to a pharmacokinetic study (Winter et al 2008) expected plasma concentrations of N-desalkylquetiapine under steady-state conditions attain about 25 % of those of the mother compound 2 h after drug intake, and metabolite concentrations are about 1.8-fold higher than those of quetiapine at the end of the dosing interval (trough concentrations). Consideration of this compound would probably result in better correlations between active moiety concentrations and receptor occupancies.…”

Section: Plasma Level Vs D 2/3 R Occupancy Relationshipmentioning

confidence: 99%

Dopamine D2/3 receptor occupancy by quetiapine in striatal and extrastriatal areas

Vernaleken

Janouschek

Raptis

et al. 2010

Int. J. Neuropsychopharm.

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Quetiapine is next to clozapine an antipsychotic agent that exerts hardly any extrapyramidal side-effects at clinical efficacious doses. Some previous receptor occupancy studies reported preferential extrastriatal D2/3 receptor (D2/3R)-binding properties of second-generation antipsychotics and suggested this as possible reason for improved tolerability. This positron emission tomography (PET) investigation was designed to compare the occupancy of dopamine D2/3Rs by quetiapine in striatal and extrastriatal brain regions. Therefore, a cohort of 16 quetiapine-treated psychotic patients underwent an [18F]fallypride (FP) PET scan. Due to the high affinity of FP and its comparatively long half-life, striatal and extrastriatal binding potentials could be determined in one single scan. Receptor occupancy was calculated as percent reduction in binding potential relative to age-matched medication-free patients suffering from schizophrenia. Quetiapine occupied 44+/-18% in the temporal cortex and 26+/-17% in the putamen, a difference significant at the level of p=0.005 (Student's t test). Quetiapine showed a mean occupancy of 36+/-16% and in the thalamus. In the caudate nucleus there was an occupancy of 29+/-16% (p=0.0072). Individual occupancy levels did not exceed 59% in any of the striatal volumes of interest. The time-interval between scan and last drug ingestion did not influence the relationship between plasma concentration and central D2/3R occupancy. Taken together, quetiapine shows preferential extrastriatal binding at D2/3Rs; the extent of this difference is comparable to that previously described for clozapine. Both antipsychotics show very low affinity for D2/3Rs.

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“…The pharmacokinetics of immediate release (IR) and extended release (XR) quetiapine fumarate and several metabolites have been characterized previously [25,26]. To demonstrate the utility of this methodology for the measurement of quetiapine and its four metabolites in human plasma, the plasma concentration-time profiles shown in Fig.…”

Section: Cross-validation Studymentioning

confidence: 99%

Development and validation of an LC–MS/MS method for the determination of quetiapine and four related metabolites in human plasma

Davis

Bravo

Gehrke

et al. 2010

Journal of Pharmaceutical and Biomedical Analysis

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Steady-State Pharmacokinetic, Safety, and Tolerability Profiles of Quetiapine, Norquetiapine, and Other Quetiapine Metabolites in Pediatric and Adult Patients with Psychotic Disorders

Cited by 68 publications

References 26 publications

Norzotepine, a Major Metabolite of Zotepine, Exerts Atypical Antipsychotic-Like and Antidepressant-Like Actions through Its Potent Inhibition of Norepinephrine Reuptake

Norzotepine, a Major Metabolite of Zotepine, Exerts Atypical Antipsychotic-Like and Antidepressant-Like Actions through Its Potent Inhibition of Norepinephrine Reuptake

Dopamine D2/3 receptor occupancy by quetiapine in striatal and extrastriatal areas

Development and validation of an LC–MS/MS method for the determination of quetiapine and four related metabolites in human plasma

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