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AIMS: The present study was designed to define the kinetic behaviour of sertraline N-demethylation in human liver microsomes and to identify the isoforms of cytochrome P450 involved in this metabolic pathway. METHODS: The kinetics of the formation of N-demethylsertraline were determined in human liver microsomes from six genotyped CYP2C19 extensive (EM) and three poor metabolisers (PM). Selective inhibitors of and specific monoclonal antibodies to various cytochrome P450 isoforms were also employed. RESULTS: The kinetics of N-demethylsertraline formation in all EM liver microsomes were fitted by a two-enzyme Michaelis-Menten equation, whereas the kinetics in all PM liver microsomes were best described by a single-enzyme Michaelis-Menten equation similar to the low-affinity component found in EM microsomes. Mean apparent Km values for the high-and low-affinity components were 1.9 and 88 microm and V max values were 33 and 554 pmol min-1 mg-1 protein, respectively, in the EM liver microsomes. Omeprazole (a CYP2C19 substrate) at high concentrations and sulphaphenazole (a selective inhibitor of CYP2C9) substantially inhibited N-demethylsertraline formation. Of five monoclonal antibodies to various cytochrome P450 forms tested, only anti-CYP2C8/9/19 had any inhibitory effect on this reaction. The inhibition of sertraline N-demethylation by anti-CYP2C8/9/19 was greater in EM livers than in PM livers at both low and high substrate concentrations. However, anti-CYP2C8/9/19 did not abolish the formation of N-demethylsertraline in the microsomes from any of the livers. CONCLUSIONS: The polymorphic enzyme CYP2C19 catalyses the high-affinity N-demethylation of sertraline, while CYP2C9 is one of the low-affinity components of this metabolic pathway.
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Pharmacol Biochem Behav. 1991 Dec;40(4):923-8.
Alcohol drinking attenuated by sertraline in rats with 6-OHDA or 5,7-DHT lesions of N. accumbens: a caloric response?
Myers RD, Quarfordt SD.
Department of Pharmacology, School of Medicine, East Carolina University, Greenville, NC 27858.
The purpose of this study was to elucidate further the role of serotonin (5-HT) in the preference for ethyl alcohol induced in the Sprague-Dawley rat by lesions of the N. accumbens. Following a standard preference test for 3-30% alcohol, dopaminergic or serotonergic neurons in the N. accumbens of the rat were lesioned bilaterally by 6-hydroxydopamine (6-OHDA) or 5,7-dihydroxytryptamine (5,7-DHT), respectively. After recovery postoperatively, each rat was offered water and its maximally preferred concentration of alcohol, which ranged from 7% to 11%. Following a 4-day pretest, either the saline control vehicle or the 5-HT reuptake inhibitor, sertraline, was injected subcutaneously in a dose of either 3.0 or 10 mg/kg b.i.d. at 0800 and 2000 h over the next 3 days. Alcohol preference during the injection sequence and for 4 days thereafter was significantly reduced by sertraline in terms of both absolute g/kg and proportion of alcohol to water intakes. Saline was without effect on alcohol drinking. Comparisons of the drinking profiles of serotonergic versus dopaminergic lesioned rats revealed a dose dependent response to sertraline only in the 5,7-DHT lesioned animals. Although sertraline did not alter water drinking, the consumption of food declined significantly during and after its administration with a decline in body weight also observed at the higher dose. These results suggest that in addition to dopaminergic neurons in the N. accumbens, the synaptic activity of 5-HT in this structure contributes to the aberrant drinking of alcohol. However, this interpretation is tempered by the fact that caloric intake was suppressed concomitantly by the drug.(ABSTRACT TRUNCATED AT 250 WORDS)
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Eur J Pharmacol. 1991 Apr 24;196(3):217-22.
Role of central serotonergic neurons in the effect of sertraline in rats in the forced swimming test.
Cervo L, Grignaschi G, Rossi C, Samanin R.
Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Sertraline, administered i.p. in single doses or as three injections in 24 h, significantly reduced the immobility of rats in the forced swimming test at 64 and 100 mumol/kg. The effect of three doses of 64 mumol/kg in 24 h was not modified in animals treated i.p. with metergoline (5 mg/kg) 3 h before testing. I.c.v. administration of 150 micrograms 5,7-dihydroxytryptamine, which depleted brain serotonin, or infusion of 6 micrograms 6-hydroxydopamine in the locus coeruleus, which markedly depleted noradrenaline in terminal regions, was also ineffective. The effect of 64 mumol/kg sertraline, once daily for 7 days, was not modified by i.c.v. 5,7-dihydroxytryptamine. The effect of three doses of 64 mumol/kg sertraline in 24 h was instead completely antagonized by 100 mg/kg sulpiride given 90 min before testing. The exact mechanism of this effect and its relevance for the favourable effects of sertraline in human depression remain to be clarified.
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