sertraline, Zoloft
Sertraline N-demethylation is catalyzed by multiple isoforms of human cytochrome P-450 in vitro.

Kobayashi K, Ishizuka T, Shimada N, Yoshimura Y, Kamijima K, Chiba K.

Laboratory of Biochemical Pharmacology and Toxicology Faculty of Pharmaceutical Sciences Chiba University, Chiba, Japan.

Sertraline, a new antidepressant of the selective serotonin reuptake inhibitor class, is extensively metabolized to desmethylsertraline in humans. We identified the cytochrome P-450 (CYP) isoforms involved in sertraline N-demethylation using pooled human liver microsomes and cDNA-expressed CYP isoforms. Eadie-Hofstee plots for the sertraline N-demethylation in human liver microsomes were monophasic. The estimated Michaelis-Menten kinetic parameters were: KM = 18.1 +/- 2.0 microM, Vmax = 0.45 +/- 0.03 nmol/min/mg of protein, and Vmax/KM = 25.2 +/- 4.3 microl/min/mg of protein. At the substrate concentration of 20 microM, which approximated the apparent KM value, sulfaphenazole (CYP2C9 inhibitor) and triazolam (CYP3A substrate) reduced the N-demethylation activities by 20 to 35% in human liver microsomes, whereas the inhibition induced by mephenytoin (CYP2C19 substrate) or quinidine (CYP2D6 inhibitor) was marginal. The anti-CYP2B6 antibody inhibited the sertraline N-demethylation activities by 35%. Sertraline N-demethylation activities were detected in all cDNA-expressed CYP isoforms studied. In particular, CYP2C19, CYP2B6, CYP2C9-Arg, CYP2D6-Val, and CYP3A4 all showed relatively high activity. When the contributions of CYP2D6, CYP2C9, CYP2B6, CYP2C19, and CYP3A4 were estimated from the Vmax/KM of cDNA-expressed CYP isoforms and from their contents in pooled human liver microsomes, the values were found to be 35, 29, 14, 13, and 9%, respectively. The results suggest that at least five isoforms of CYP (CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4) are involved in the sertraline N-demethylation in human liver microsomes and that the contribution of any individual isoform does not exceed 40% of overall metabolism. Therefore, concurrent administration of a drug that inhibits a specific CYP isoform is unlikely to cause a marked increase in the plasma concentration of sertraline.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10383917&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Relaxant effects of antidepressants on human isolated mesenteric arteries.

Vila JM, Medina P, Segarra G, Lluch P, Pallardo F, Flor B, Lluch S.

Department of Physiology, University of Valencia, Spain. vila post.uv.es

AIMS: The therapeutic action of tricyclic agents may be accompanied by unwanted effects on the cardiovascular system. The evidence for the effects on vascular and nonvascular smooth muscle comes from animal studies. Whether these studies can be extrapolated to human vessels remains to be determined. Therefore, the present study was designed to investigate the influence of amitriptyline, nortriptyline and sertraline on the contractile responses of human isolated mesenteric arteries to electrical field stimulation, noradrenaline and potassium chloride. METHODS: Arterial segments (lumen diameter 0.8-1.2 mm) were obtained from portions of the human omentum during the course of 41 abdominal operations (22 men and 19 women), and rings 3 mm long were mounted in organ baths for isometric recording of tension. In some artery rings the endothelium was removed mechanically. RESULTS: In precontracted artery rings amitriptyline, nortriptyline and sertraline (3x10(-7)-10(-4) m ) produced concentration-dependent relaxation that was independent of the presence or absence of vascular endothelium. Incubation with indomethacin (3x10(-6) m ) reduced the pD2 values thus indicating the participation of dilating prostanoid substances in this response. Amitriptyline and nortriptyline inhibited both the neurogenic-and noradrenaline-induced contractions. In contrast, only the highest concentration of sertraline reduced the adrenergic responses. Amitriptyline, nortriptyline and sertraline inhibited contractions elicited by KCl and produced rightward shifts of the concentration-response curve to CaCl2 following incubation in calcium-free solution. CONCLUSIONS: These results indicate that amitriptyline and nortriptyline could act as adrenoceptor antagonists and direct inhibitors of smooth muscle contraction of human mesenteric arteries, whereas sertraline might principally exert its action only as direct inhibitor of smooth muscle contraction. This relaxant mechanism involves an interference with the entry of calcium.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10417500&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
The influence of selective serotonin reuptake inhibitors (SSRIs) on the pharmacokinetics of thioridazine and its metabolites: in vivo and in vitro studies.

Daniel WA, Syrek M, Haduch A, Wojcikowski J.

Department of Pharmacokinetics and Drug Metabolism, Institute of Pharmacology, Polish Academy of Sciences, Krakow.

Due to its psychotropic profile, thioridazine is a neuroleptic suitable for a combination with antidepressants in a number of complex psychiatric illnesses. However, because of its serious side-effects, such a combination with selective serotonin reuptake inhibitors (SSRIs) which inhibit cytochrome P-450 may be dangerous. The aim of the present study was to investigate a possible impact of SSRIs on the pharmacokinetics and metabolism of thioridazine in a steady state in rats. Thioridazine (10 mg/kg) was injected intraperitoneally, twice a day, for two weeks, alone or jointly with one of the antidepressants (fluoxetine, fluvoxamine or sertraline). Concentrations of thioridazine and its main metabolites (2-sulfoxide = mesoridazine; 2-sulfone = sulforidazine; 5-sulfoxide = ring sulfoxide and N-desmethylthiorid-azine) were assessed in the blood plasma and brain at 30 min, 6 and 12 h after the last dose of the drugs using an HPLC method. Fluoxetine potently increased (up to 13 times!) the concentrations of thioridazine and its metabolites in the plasma, especially after 6 and 12 h. Moreover, an increase in the sum of concentrations of tioridazine + metabolites and thioridazine/metabolite ratios was observed. In vitro studies with control liver microsomes, as well as with microsomes of rats treated chronically with fluoxetine show that the changes in the thioridazine pharmacokinetics may be attributed to the competitive (N-demethylation, Ki = 23 microM) and mixed inhibition (2- and 5-sulfoxidation, Ki = 60 microM and 34 microM, respectively) of thioridazine metabolism by fluoxetine, and to the adaptive changes produced by chronic administration of fluoxetine, as reflected by inhibition of N-demethylation and formation of sulforidazine. Sertraline seemed to have a tendency to decrease thioridazine concentration in vivo, though in vitro studies showed that - like fluoxetine - it competitively or via mixed mechanism inhibited the three metabolic pathways of thioridazine (Ki = 41 microM, 64 microM and 47 microM, respectively). Chronic treatment with sertraline stimulated thioridazine 2- and 5-sulfoxidation, which may be responsible for the observed tendency of sertraline to decrease concentrations of the neuroleptic. In the case of fluvoxamine, a tendency to increase the thioridazine level was observed, which may be connected with the competitive or mixed inhibition of thioridazine N-demethylation and 2-sulfoxidation by the antidepressant (Ki = 17 microM and 167 microM, respectively). Repeated administration of fluvoxamine did not produce any changes in the activity of thioridazine-metabolizing enzymes. In conclusion, of the SSRIs studied, only fluoxetine produces a substantial increase in the thioridazine level in the plasma and brain. In the case of fluvoxamine, a tendency to increase the thioridazine level should be considered. Coadministration of thioridazine and sertraline seems to be safe, though a tendency to decrease the thioridazine level may be expected.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10445388&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Inhibition and possible induction of rat CYP2D after short- and long-term treatment with antidepressants.

Daniel WA, Haduch A, Wojcikowski J.

Polish Academy of Sciences, Institute of Pharmacology, Smetna 12, 31-343 Krakow, Poland.

The aim of this study was to investigate the influence of tricyclic antidepressants (imipramine, amitriptyline, clomipramine, desipramine), selective serotonin reuptake inhibitors (SSRIs: fluoxetine, sertraline) and novel antidepressant drugs (mirtazapine, nefazodone) on the activity of CYP2D, measured as a rate of ethylmorphine O-deethylation. The reaction was studied in control liver microsomes in the presence of the antidepressants, as well as in microsomes of rats treated intraperitoneally for one day or two weeks (twice a day) with pharmacological doses of the drugs (imipramine, amitriptyline, clomipramine, nefazodone 10 mg kg(-1) i.p.; desipramine, fluoxetine, sertraline 5 mg kg(-1) i.p.; mirtazapine 3 mg kg(-1) i.p.), in the absence of the antidepressants in-vitro. Antidepressants decreased the activity of the rat CYP2D by competitive inhibition of the enzyme, the potency of their inhibitory effect being as follows: clomipramine (K(i) = 14 microM) > sertraline approximate, equals fluoxetine (K(i) = 17 and 16 microM, respectively) > imipramine approximate, equals amitriptyline (K(i) = 26 and 25 microM, respectively) > desipramine (K(i) = 44 microM) > nefazodone (K(i) = 55 microM) > mirtazapine (K(i) = 107 microM). A one-day treatment with antidepressants caused a significant decrease in the CYP2D activity after imipramine, fluoxetine and sertraline. After prolonged administration of antidepressants, the decreased CYP2D activity produced by imipramine, fluoxetine and sertraline was still maintained. Moreover, amitriptyline and nefazodone significantly decreased, while mirtazapine increased the activity of the enzyme. Desipramine and clomipramine did not produce any effect when administered in-vivo. The obtained results indicate three different mechanisms of the antidepressants-CYP2D interaction: firstly, competitive inhibition of CYP2D shown in-vitro, the inhibitory effects of tricyclic antidepressants and SSRIs being stronger than those of novel drugs; secondly, in-vivo inhibition of CYP2D produced by both one-day and chronic treatment with tricyclic antidepressants (except for desipramine and clomipramine) and SSRIs, which suggests inactivation of the enzyme apoprotein by reactive metabolites; and thirdly, in-vivo inhibition by nefazodone and induction by mirtazapine of CYP2D produced only by chronic treatment with the drugs, which suggests their influence on the enzyme regulation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12495558&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
In-vitro activity of psychiatric drugs against Corynebacterium urealyticum (Corynebacterium group D2).

Munoz-Bellido JL, Munoz-Criado S, Garcia-Rodriguez JA.

Departamento de Microbiologia y Parasitologia, Hospital Universitario de Salamanca, Spain.

We tested the in-vitro activity of amoxycillin, amoxycillin/clavulanic acid, cefotaxime, gentamicin, trimethoprim-sulphamethoxazole, tetracycline, norfloxacin, ciprofloxacin, vancomycin, teicoplanin, clindamycin and five psychiatric drugs (chlorpromazine, sertraline, fluoxetine, paroxetine and risperidone) against 32 strains of Corynebacterium urealyticum. Resistance rates exceeded 90% for all antibiotics except glycopeptides, quinolones and tetracycline. Sertraline was the most active psychiatric drug. We tested the influence of sertraline on the activity of amoxycillin, amoxycillin/clavulanic acid, cefotaxime, gentamicin, trimethoprim-sulphamethoxazole, tetracycline and ciprofloxacin. We did not observe antagonism in any case. Sertraline enhanced the activity of ciprofloxacin and tetracycline against all strains (MIC decrease: 4-64-fold for ciprofloxacin, 2-32-fold for tetracycline).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8737151&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Review of clinical use of sertraline by family practice physicians in a small Air Force hospital.

Bourgeois JA.

60th Medical Group (SGOHN), David Grant Medical Center, Travis Air Force Base, CA 94535, USA.

The clinical use of sertraline for 1 year in a family practice clinic in a small Air Force hospital was reviewed. Retrospective chart review showed that 85% of patients receiving five or more prescriptions for sertraline had a diagnosis of depression; the remainder were treated for chronic pain or dysthymia. The patients in the review needed dose increases (above the recommended starting dose of 50 mg qd) in nearly 50% of the cases. Clinicians using sertraline for the treatment of affective illness in the primary care setting should be aware of the likelihood for dose increases to achieve maximal clinical benefit.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8754718&dopt=Abstract sertraline Zoloft



sertraline, Zoloft
Analysis of sertraline-only overdoses.

Klein-Schwartz W, Anderson B.

Maryland Poison Center, Department of Pharmacy Practice and Science, University of Maryland School of Pharmacy, Baltimore 21201, USA.

Sertraline is an antidepressant for which preliminary data suggest a low inherent toxicity. Previously reported case series have included coingestants or had small numbers of patients. This study was undertaken to determine the toxicity of overdoses of sertraline alone. A 2-year retrospective and 6-month prospective study was conducted at a regional poison center. There were 52 patients with a mean age of 19.3 +/- 13.8 years and a mean dose of 727 +/- 686 mg. There were no symptoms in 34 cases. Symptomatic patients experienced mild central nervous system, cardiovascular, and gastrointestinal effects. Two patients developed bradycardia which resolved without therapy. While all but 3 of 38 adolescents and adults were treated in a health care facility, 10 of 14 children were managed at home. Gastrointestinal decontamination was performed in 37 cases. No other specific therapy was required. Serious toxicity would not be expected following sertraline-only overdoses.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8765108&dopt=Abstract sertraline Zoloft