The effect of age on the pharmacokinetics of zotepine and its metabolite norzotepine in healthy volunteers

Velagapudi, Raja; Faulkner, Robert; Hinson, James L.; Leone, M.B.; Ghani, Sajda; Moult, J.T.

doi:10.1016/s0006-3223(97)87078-3

Biological Psychiatry

1997

DOI: 10.1016/s0006-3223(97)87078-3

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The effect of age on the pharmacokinetics of zotepine and its metabolite norzotepine in healthy volunteers

Raja Velagapudi¹,

Robert Faulkner²,

James L. Hinson³

et al.

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“…Some reports have been published regarding plasma concentration of norZTP in humans. In one study conducted with 12 young healthy subjects, plasma concentration of norZTP was measured, and C max value of norZTP was approximately 30% of the parent compound in plasma (ZTP at 12.7 ng/ml versus norZTP at 3.79 ng/ml) after administration of 50 mg of ZTP (Velagapudi et al, 1997). Similar results were observed in a schizophrenia patient (Chou et al, 2005).…”

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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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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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Erratum to: Zotepine: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of schizophrenia

Prakash¹,

Lamb²

1998

CNS Drugs

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The effect of age on the pharmacokinetics of zotepine and its metabolite norzotepine in healthy volunteers

Cited by 2 publications

References 0 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

Erratum to: Zotepine: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in the management of schizophrenia

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