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Titolo:
The effect of selective serotonin reuptake inhibitors (SSRIs) on the pharmacokinetics and metabolism of perazine in the rat
Autore:
Daniel, WA; Syrek, M; Haduch, A; Wojcikowski, J;
Indirizzi:
Polish Acad Sci, Inst Pharmacol, PL-31343 Krakow, Poland Polish Acad Sci Krakow Poland PL-31343 harmacol, PL-31343 Krakow, Poland
Titolo Testata:
JOURNAL OF PHARMACY AND PHARMACOLOGY
fascicolo: 4, volume: 53, anno: 2001,
pagine: 449 - 461
SICI:
0022-3573(200104)53:4<449:TEOSSR>2.0.ZU;2-0
Fonte:
ISI
Lingua:
ENG
Soggetto:
5-HT RECEPTOR SUBPOPULATIONS; HUMAN LIVER-MICROSOMES; IN-VITRO; DEBRISOQUIN HYDROXYLATION; PHARMACOLOGICAL TREATMENT; FLUOXETINE; FLUVOXAMINE; ANTIDEPRESSANTS; SERTRALINE; SCHIZOPHRENIA;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
47
Recensione:
Indirizzi per estratti:
Indirizzo: Daniel, WA Polish Acad Sci, Inst Pharmacol, Smetna 12, PL-31343 Krakow, Poland Polish Acad Sci Smetna 12 Krakow Poland PL-31343 rakow, Poland
Citazione:
W.A. Daniel et al., "The effect of selective serotonin reuptake inhibitors (SSRIs) on the pharmacokinetics and metabolism of perazine in the rat", J PHARM PHA, 53(4), 2001, pp. 449-461

Abstract

The aim of this study was to investigate the effect of three selective serotonin reuptake inhibitors (SSRIs), fluoxetine, fluvoxamine and sertraline,on the pharmacokinetics and metabolism of perazine in a steady stale in rats. Perazine (10 mg kg(-1), i.p.) was administered twice daily for two weeks, alone or jointly with one of the SSRIs. Concentrations of perazine and its two main metabolites (N-desmethylperazine and 5-sulfoxide) in the plasmaand brain were measured 30 min and 6 and 12 h after the last dose of the drugs. Of the investigated SSRIs, fluoxetine and fluvoxamine significantly increased plasma and brain concentrations of perazine (up to 900 % and 760 %of the control value, respectively), their effect being most pronounced after 30 min and 6 h. Moreover, simultaneous increases in perazine metabolites concentrations and in the perazine/metabolite concentration ratios were observed. Sertraline elevated plasma and brain concentrations of perazine after 30 min. In-vitro studies with liver microsomes of rats treated chronically with perazine, SSRIs or their combinations showed decreased concentrations of cytochrome P-450 after perazine and a combination of perazine and fluvoxamine (vs control), and increased concentration after a combination of perazine and fluoxetine (vs perazine-treated group). Prolonged treatment with perazine did not significantly change the rate of its own metabolism. Chronic administration of fluoxetine or sertraline, alone or in a combinationwith perazine, accelerated perazine N-demethylation (vs control or perazine group, respectively). Fluvoxamine had a similar effect. The 5-sulfoxidation of perazine was accelerated by fluvoxamine and sertraline treatment, butthe process was inhibited by administration of a combination of perazine and fluoxetine or fluvoxamine (vs control). Kinetic studies using control liver microsomes, in the absence or presence of SSRIs added in-vitro, demonstrated competitive inhibition of both N-demethylation and sulfoxidation by the investigated SSRIs. Sertraline was the most potent inhibitor of perazineN-demethylation but the weakest inhibitor of sulfoxidation. Results of in-vivo and in-vitro studies indicate that the observed interaction between perazine and SSRIs mainly involves competition for an active site of perazineN-demethylase and sulfoxidase. Moreover, increases in the concentrations of both perazine and metabolites measured, produced by the investigated drugcombinations in-vivo, suggest simultaneous inhibition of another, yet to be investigated, metabolic pathway of perazine (e.g. aromatic hydroxylation).

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Documento generato il 06/04/20 alle ore 01:14:39