sertraline, Zoloft
Comparison of the effects of sertraline and its metabolite desmethylsertraline on blockade of central 5-HT reuptake in vivo.

Sprouse J, Clarke T, Reynolds L, Heym J, Rollema H.

Department of Neuroscience, Pfizer Central Research, Groton, CT 06340, USA.

N-demethylation of the selective serotonin reuptake inhibitor sertraline to desmethylsertraline yields a compound with 10- to 20-fold less potency at blocking serotonin (5-HT) reuptake as measured in vitro. In the present study desmethylsertraline (DMS) was examined in two in vivo models of reuptake inhibition--elevation of extracellular 5-HT in the corpus striatum as measured by microdialysis and inhibition of firing of serotonin-containing dorsal raphe neurons. Whereas sertraline (1, 3.2, and 10 mg/kg s.c.) produced a dose-dependent increase in extracellular 5-HT and a decrease in 5-HIAA in rat striatum, desmethylsertraline was without effect on either parameter. In similar fashion, desmethylsertraline had no effect on dorsal raphe cell firing at a dose (1,000 micrograms/kg i.v.) nearly 20-fold the ED50 for sertraline (52 micrograms/kg). Taken together, these data suggest that DMS does not contribute to the blockade of central 5-HT reuptake produced by sertraline in vivo and therefore would be expected to play a negligible role in its clinical activity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8924190&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Effects of tianeptine, sertraline and clomipramine on brain serotonin metabolism: a voltammetric approach in the rat.

Marinesco S, Poncet L, Debilly G, Jouvet M, Cespuglio R.

Departement de Medecine Experimentale, Universite Claude Bernard, Lyon, France.

Tianeptine is a substance enhancing the serotonir uptake while sertraline and clomipramine inhibit it. By means of 5-hydroxyin-doleacetic acid (5-HIAA) voltammetric measurements, this study investigated their influence on serotonin metabolism which depends mainly upon the activity of monoamine oxidase type A. After tianeptine injection the 5-HIAA signal increased by about 60%. This effect was maintained when the animals were pre-treated with MDL 72145 (an inhibitor of monoamine oxidase type B) but reduced when clorgyline (an inhibitor of monoamine oxidase type A) was administered after tianeptine. Administration of sertraline or clomipramine reduced the 5-HIAA signal by about 30-50%, whether the animals were pre-treated with MDL 72145 or not. It is to be concluded that tianeptine, sertraline and clomipramine can regulate the 5-HT fraction present in the synaptic cleft, not only by acting at the level of the serotoninergic neurons, but also by favoring or reducing the access of the amine to monoamine oxidase type A which is synthesized within non-serotoninergic neurons and glial cells.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8930312&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
The disposition of fluoxetine but not sertraline is altered in poor metabolizers of debrisoquin.

Hamelin BA, Turgeon J, Vallee F, Belanger PM, Paquet F, LeBel M.

School of Pharmacy, Universite Laval, Quebec Heart Institute, Laval Hospital, Sainte-Foy, Canada.

BACKGROUND: Substrates and inhibitors of the cytochrome P450 isozyme CYP2D6 have overlapping structural characteristics. Two prototype serotonin uptake inhibitors, sertraline and fluoxetine, share these structural criteria and have been identified as potent inhibitors of CYP2D6 in vitro. The current study was undertaken to investigate whether genetically determined CYP2D6 activity alters the disposition of sertraline or fluoxetine or both. METHODS: Single doses of sertraline (50 mg) and fluoxetine (20 mg) were administered successively to 20 young men with high (extensive metabolizers; n = 10) and low (poor metabolizers; n = 10) CYP2D6 activity. Blood and urine samples were collected for 5 to 7 half-lives and sertraline, desmethylsertraline, fluoxetine, and norfluoxetine were determined by GC and HPLC techniques. RESULTS: Poor metabolizers had significantly greater fluoxetine peak plasma concentrations (Cmax; increases 57%), area under the concentration versus time curve (AUCzero-->infinity; increases 290%), and terminal elimination half-life (increases 216%) compared with extensive metabolizers. The total amount of fluoxetine excreted in the urine during 8 days was almost three times higher in poor metabolizers than in extensive metabolizers (719 versus 225 micrograms; p < 0.05), whereas the total amount of norfluoxetine excreted in urine of poor metabolizers was about half of that of extensive metabolizers (524 versus 1047 micrograms; p < 0.05). Norfluoxetine Cmax and AUCzero-->t were significantly smaller in poor metabolizers (decreases 55% and decreases 53%, respectively), and the partial metabolic clearance of fluoxetine into norfluoxetine was 10 times smaller in this group (4.3 +/- 1.9 versus 0.4 +/- 0.1 L/hr; p < 0.05). No significant differences between extensive and poor metabolizers were found for sertraline and desmethylsertraline pharmacokinetics. CONCLUSION: These data indicate that poor metabolizers accumulate fluoxetine but not sertraline and that CYP2D6 plays an important role in the demethylation of fluoxetine but not of sertraline.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8941024&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
HPLC of sertraline and norsertraline in plasma or serum.

Patel J, Spencer EP, Flanagan RJ.

Poisons Unit, Guy's and St Thomas' Hospital Trust, London, UK.

A simple method for the measurement of sertraline and norsertraline in plasma or serum suitable for use in single-dose pharmacokinetic studies has been developed. Internal standard solution, aqueous fenethazine (10 mg/L) (20 microL), and Tris buffer (2 mol/L), pH 10.6) (100 microL) were added to plasma (200 microL). Sertraline, norsertraline and the internal standard were extracted into methyl tert-butyl ether (200 microL) by mixing (30 s) and centrifugation (11,000 r.p.m., 4 min). A portion (100 microL) of the extract was injected onto a Spherisorb S5SCX HPLC column (150 x 4.6 mm i.d.) which was eluted with methanol:water (19 + 1) containing ammonium perchlorate (40 mmol/L), final pH 7.0. Detection was by UV monitoring (215 nm). The concentration of each analyte in each sample was calculated from the calibration graph (peak-height ratio of analyte to that of the internal standard against concentration) obtained after analysis of plasma samples containing known amounts of sertraline and norsertraline. The limit of accurate measurement of the assay was 10 micrograms/L) sertraline and 20 micrograms/L) norsertraline.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8949919&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
The stimulatory and inhibitory components of cocaine's actions on the 5-HTP-induced 5-HT2A receptor response.

Darmani NA, Reeves SL.

Department of Pharmacology, Kirksville College of Osteopathic Medicine, MO 63501, USA.

Previously we have shown that cocaine attenuates the 5-HT2A receptor-mediated head-twitch response (HTR) in mice produced by the 5-HT2A/C direct agonist (+/-)-1 (2.5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI). This inhibition appears to be due to cocaine-induced indirect stimulation of the inhibitory serotonergic 5-HT1A and noradrenergic alpha 2 receptors via the inhibition of reuptake of synaptic serotonin (5-HT) and norepinephrine (NE), respectively. In the present study, we investigated the effects of cocaine, its phenyltropane analogue WIN 35428, and the selective 5-HT (sertraline). NE (nisoxetine) and dopamine (DA) (GBR 12935) reuptake inhibitors on the 5-hydroxytryptophan (5-HTP)-induced HTR. We utilized two experimental protocols where cocaine or the cited drugs were administered either after (protocol 1) or prior (protocol 2) to 5-HTP injection. Cocaine in both protocols produced a dose-dependent enhancement in the 5-HTP-induced HTR (ED50 4.68 +/- 1.21 and 3.55 +/- 1.31, respectively). Sertraline was more potent (ED50 2.64 +/- 1.1 and 2.1 +/- 1.54, respectively) in enhancing the induced behavior and dose by dose produced greater (3 to 10 times) HTRs than cocaine. On the other hand, nisoxetine dose dependently and completely attenuated the induced behavior (ID50 3.33 +/- 1.32 and 1.72 +/- 1.34, respectively), whereas GBR 12935 only at high doses (ID50 15.34 +/- 1.52 and 11.91 +/- 1.3, respectively) decreased the induced response. The inability of cocaine to induce as many HTRs as sertraline appears to lie in its ability to also indirectly stimulate the inhibitory 5-HT1A and alpha 2 receptors because the stimulant caused greater enhancement in the 5-HTP-induced HTRs in the presence of their corresponding antagonists [S(-)-UH 301 and yohimbine, respectively]. WIN 35428 was more potent (ED50 2.87 +/- 1.3 and 1.79 +/- 1.1 for protocols 1 and 2, respectively) in stimulating the 5-HTP-induced HTR and produced a bell-shaped dose-response curve. The results indicate that cocaine enhances the 5-HTP-induced HTR via the inhibition of synaptic 5-HT reuptake. The stimulant also simultaneously attenuates the induced behavior by indirect simulation of the serotonergic 5-HT1A and noradrenergic alpha 2 receptors via inhibition of reuptake of the corresponding monoamines.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8951980&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Improved CEDIA benzodiazepine assay eliminates sertraline crossreactivity.

Fitzgerald RL, Herold DA.

Veterans Affairs Medical Center, San Diego, California 92161, USA. rlfitzgerald vapop.ucsd.edu

Initial experiments demonstrated that the original CEDIA (cloned enzyme donor immunoassay) benzodiazepine assay crossreacted with setraline and sertraline metabolites. In response to this phenomenon, Boehringer Mannheim Corporation developed an improved CEDIA benzodiazepine assay in order to eliminate sertraline crossreactivity. The improved CEDIA assay was evaluated against the original CEDIA product, EMIT II (enzyme multiplied immunoassay technique) benzodiazepine assay, and electron capture negative chemical ionization (ECNCI) gas chromatography-mass spectrometry (GC-MS). Five hundred and thirty-one urine drug screens were tested by the immunoassays. Sensitivity and specificity of these immunoassays for the 5-aryl-7-chloro-1,4-benzodiazepine compounds were 92 and 98%, respectively, for the improved CEDIA assay; 92 and 93%, respectively, for the current CEDIA assay; and 87 and 98%, respectively, for EMIT II. The improved CEDIA assay performed almost identically to the EMIT II assay, both of which had a significant advantage over the original CEDIA product, which was subject to crossreactivity because of sertraline metabolites. The alpha-hydroxy ketone metabolites of sertraline are identified in human urine specimens for the first time using ECNCI GC-MS.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9013289&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Contribution of lysosomal trapping to the total tissue uptake of psychotropic drugs.

Daniel WA, Wojcikowski J.

Polish Academy of Sciences, Institute of Pharmacology, Krakow, Poland.

The present study was aimed at assessing individual contributions of the phospholipid binding and lysosomal trapping to the total tissue uptake of psychotropic drugs with different chemical structures, such as promazine, imipramine, amitriptyline, fluoxetine, sertraline (basic lipophilic drugs) and carbamazepine (lipophilic, but not basic). We also tried to find out whether lysosomal trapping may be involved in the pharmacokinetic interactions in clinical combinations of psychotropics. Uptake experiments were carried out on slices of various rat tissues as a system with intact lysosomes. Initial concentration of each drug was 5 microM. The results were compared with those obtained in the presence of the "lysosomal inhibitors", ammonium chloride or monensin. The basic lipophilic psychotropics showed high uptake in tissues known for the abundance of lysosomes, mainly the lungs. The highest drug accumulation was found for promazine and amitriptyline. "Lysosomal inhibitors" significantly decreased the uptake of the basic lipophilic drugs, particularly in the lungs and liver. The most potent effect was observed for amitriptyline, imipramine and promazine. The brain showed moderate accumulation of basic lipophilic psychotropics and the effect of the "lysosomal inhibitors" was significant only in the case of amitriptyline, imipramine and sertraline. The only exception to the above regularity were imipramine and sertraline which were taken up more extensively by the adipose tissue than by lysosome-rich tissues such as the lungs or liver. Carbamazepine did not show lysosomotropism. Amitriptyline and promazine mutually decreased their uptake by lung slices when the drugs were incubated jointly. In the presence of ammonium chloride the interaction did not occur. In conclusion, the obtained results show that (1) the lysosomal trapping is an important factor determining the distribution of the basic lipophilic psychotropics; however (2) their tissue uptake depends more on the phospholipid binding than on the lysosomal trapping; (3) the lysosomal trapping may be involved in the pharmacokinetic interactions between psychotropics.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9060036&dopt=Abstract sertraline Zoloft