In Vitro and In Vivo Studies on the Disposition of Mirtazapine in Humans

Dahl, Marja­‐Liisa; Voortman, G.; Alm, Christina; Elwin, Carl‐Eric; Delbressine, L. P. C.; Vos, R.M.E.; Bogaards, J.J.P.; Bertilsson, Leif

doi:10.2165/00044011-199713010-00005

Cited by 63 publications

(47 citation statements)

References 16 publications

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“…82 Further clinical studies are warranted on the impact of CYP2D6 on mirtazapine clinical effects and adverse events, which differ between both enantiomers.…”

Section: Impact Of Cyp2d6 Polymorphisms On Dosing Of Antidepressantsmentioning

confidence: 99%

Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response

et al. 2004

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Genetic factors contribute to the phenotype of drug response. We systematically analyzed all available pharmacogenetic data from Medline databases on the impact that genetic polymorphisms have on positive and adverse reactions to antidepressants and antipsychotics. Additionally, dose adjustments that would compensate for genetically caused differences in blood concentrations were calculated. To study pharmacokinetic effects, data for 36 antidepressants were screened. We found that for 20 of those, data on polymorphic CYP2D6 or CYP2C19 were found and that in 14 drugs such genetic variation would require at least doubling of the dose in extensive metabolizers in comparison to poor metabolizers. Data for 38 antipsychotics were examined: for 13 of those CYP2D6 and CYP2C19 genotype was of relevance. To study the effects of genetic variability on pharmacodynamic pathways, we reviewed 80 clinical studies on polymorphisms in candidate genes, but those did not for the most part reveal significant associations between neurotransmitter receptor and transporter genotypes and therapy response or adverse drug reactions. In addition associations found in one study could not be replicated in other studies. For this reason, it is not yet possible to translate pharmacogenetic parameters fully into therapeutic recommendations. At present, antidepressant and antipsychotic drug responses can best be explained as the combinatorial outcome of complex systems that interact at multiple levels. In spite of these limitations, combinations of polymorphisms in pharmacokinetic and pharmacodynamic pathways of relevance might contribute to identify genotypes associated with best and worst responders and they may also identify susceptibility to adverse drug reactions.

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“…82 Further clinical studies are warranted on the impact of CYP2D6 on mirtazapine clinical effects and adverse events, which differ between both enantiomers.…”

Section: Impact Of Cyp2d6 Polymorphisms On Dosing Of Antidepressantsmentioning

confidence: 99%

Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response

et al. 2004

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“…13-Hydroxymirtazapine has been reported in metabolism studies with mice (Delbressine and Vos, 1997). In human liver microsomal fractions, 8-hydroxymirtazapine, N-desmethylmirtazapine, and mirtazapine N-oxide were formed (Dahl et al, 1997). Pharmacokinetic data indicated that N-desmethylmirtazapine has activity similar to that of the parent drug; however, the activity is 5 to 10 times less than that of mirtazapine .…”

Section: Introductionmentioning

confidence: 99%

“…Since it is assumed that metabolism of this drug takes place mainly in the liver (Sandker et al, 1994), metabolic studies have been undertaken using human liver and rat hepatocytes and human liver microsomes (Sandker et al, 1994;Dahl et al, 1997). Phase I and II human metabolites reported were mirtazapine-N-oxide, 8-hydroxymirtazapine, N-desmethylmirtazapine, mirtazapine N-glucuronide, mirtazapine N-sulfate, 8-hydroxymirtazapine glucuronide, 8-hydroxy-N-desmethylmirtazapine, 8-hydroxy-N-desmethylmirtazapine glucuronide, 8-hydroxymirtazapine sulfate, and 8-hydroxy-N-desmethylmirtazapine sulfate.…”

mentioning

confidence: 99%

“…In the antidepressant drug mianserin, which differs from mirtazapine in that a carbon atom replaces the N-6 of mirtazapine, metabolism studies indicate that the R(Ϫ)-enantiomer is metabolized to demethylated products whereas the S(ϩ)-enantiomer is metabolized to 8-hydroxy products (Heinig and Blaschke, 1993). The metabolism is mediated by cytochrome P450; enantiomeric differences are accredited to the effects of various CYP450 isoforms involved (Dahl et al, 1997;Delbressine et al, 1998).…”

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confidence: 99%

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Biotransformation of Mirtazapine byCunninghamella Elegans

Moody¹,

Freeman²,

Fu³

et al. 2002

Drug Metab Dispos

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ABSTRACT:The fungus Cunninghamella elegans was used as a microbial model of mammalian metabolism to biotransform the tetracyclic antidepressant drug mirtazapine, which is manufactured as a racemic mixture of R(؊)-and S(؉)-enantiomers. In 168 h, C. elegans transformed 91% of the drug into the following seven metabolites: 8-hydroxymirtazapine, N-desmethyl-8-hydroxymirtazapine, N-desmethylmirtazapine, 13-hydroxymirtazapine, mirtazapine N-oxide, 12-hydroxymirtazapine, and N-desmethyl-13-hydroxymirtazapine. Circular dichroism spectral analysis of unused mirtazapine indicated that it was slightly enriched with the R(؊)-enantiomer. When the fungus was treated with the optically pure forms of the drug, the S(؉)-enantiomer produced all seven metabolites whereas the R(؊)-enantiomer produced only 8-hydroxymirtazapine, N-desmethyl-8-hydroxymirtazapine, N-desmethylmirtazapine, and mirtazapine N-oxide. C. elegans produced five mammalian and two novel metabolites and is therefore a suitable microbial model for mirtazapine metabolism.The antidepressant drug mirtazapine (1,2,3,4,10,14b-hexahydro-2-methylpyrazino[2,1-a]pyrido[2,3-c]benzazepine), marketed as RE-MERON SolTab, has a tetracyclic chemical structure ( Fig. 1) that is unlike those of selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, or tricyclic antidepressants. It also has a different mode of action. Mirtazapine acts as an antagonist of ␣ 2 -adrenergic autoreceptors and heteroreceptors, resulting in increased release of norepinephrine and serotonin (Puzantian, 1998). Therefore, it has been regarded as a noradrenergic and specific serotonergic antidepressant (Westenberg, 1999). Mirtazapine is also an antagonist of postsynaptic serotonin type 2 (5-HT 2 ) 1 and type 3 (5-HT 3 ), but not type 1 (5-HT 1 ) receptors, decreasing unwanted side effects (Stimmel et al., 1997). The drug has a high affinity for histamine H 1 receptors, causing it to act as a sedative (Puzantian, 1998).Mirtazapine is commercially available as a racemic mixture of the S(ϩ)-and R(Ϫ)-enantiomers (Fig. 1). The S(ϩ)-enantiomer is responsible for blocking ␣ 2 activity and is the more potent 5-HT 2 antagonist (McGrath et al., 1998). The R(Ϫ)-enantiomer is responsible for the 5-HT 3 antagonist activity and contributes equally to the blocking of ␣ 2 -heteroreceptors (McGrath et al., 1998). Both enantiomers function as antihistamines (Stimmel et al., 1997).Since it is assumed that metabolism of this drug takes place mainly in the liver (Sandker et al., 1994), metabolic studies have been undertaken using human liver and rat hepatocytes and human liver microsomes (Sandker et al., 1994;Dahl et al., 1997). Phase I and II human metabolites reported were mirtazapine-N-oxide, 8-hydroxymirtazapine, N-desmethylmirtazapine, mirtazapine N-glucuronide, mirtazapine N-sulfate, 8-hydroxymirtazapine glucuronide, 8-hydroxy-N-desmethylmirtazapine, 8-hydroxy-N-desmethylmirtazapine glucuronide, 8-hydroxymirtazapine sulfate, and 8-hydroxy-N-desmethylmirtazapine sulfate. The same metabolites are also produced...

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“…Nesta concentração foram encontrados valores de precisão e exatidão de 11,4% e 15,0%, respectivamente, para a MTZ e 9,0% e 18,4% para a DMTZ. Esse limite de quantificação, embora superior aos valores relatados por alguns autores na literatura (Ptáek, Klíma, Macek, 2003;Maris, Dingler, Niehues, 1999;Morgan, Tapper, Spencer, 2003), é adequado para utilização do método em estudos de disposição cinética (Dahl et al, 1997).…”

Section: Validação Do Métodounclassified

Análise simultânea da mirtazapina e N-desmetilmirtazapina em plasma empregando a cromatografia líquida de alta eficiência

Briguenti

Bonato

2005

Rev. Bras. Cienc. Farm.

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INTRODUÇÃOA mirtazapina (MTZ) é um novo antidepressivo, membro da classe das piperazinoazepinas, que possui modo de ação diferente de qualquer outro antidepressivo utilizado atualmente. A MTZ tem dupla ação, aumentando a atividade central noradrenérgica e serotoninérgica, através do bloqueio de receptores α 2 e do antagonismo seletivo de receptores 5HT 2 e 5HT 3 . (Fawcett, Barkin, 1998;Nutt, 1997; Sussman, Stahal, 1996). Devido à sua meia-vida de eliminação, de 20 a 40 horas, a MTZ é administrada em uma dose única diária que varia de 15 a 45 mg, resultando em concentrações plasmáticas de 5 a 100 ng/mL (Timmer, Ad Sitsen, Delbressine, 2000;Fawcett, Barkin, 1998).O metabolismo da MTZ já foi estudado em várias espécies de animais, bem como em humanos (Sandker et al., 1994). As principais vias do metabolismo da MTZ são a N-desmetilação, a N-oxidação e 8-hidroxilação, seguidas de conjugação. A MTZ também sofre conjugação direta com uma glicoronida, formando um derivado amônio quaternário (N + ) (Caccia, 1998; Timmer, Ad Sitsen,

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In Vitro and In Vivo Studies on the Disposition of Mirtazapine in Humans

Cited by 63 publications

References 16 publications

Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response

Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response

Biotransformation of Mirtazapine byCunninghamella Elegans

Análise simultânea da mirtazapina e N-desmetilmirtazapina em plasma empregando a cromatografia líquida de alta eficiência

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