Pharmacokinetics and Biotransformation of Mirtazapine in Human Volunteers

Delbressine, L. P. C.; Moonen, Martial; Kaspersen, Frans M.; Wagenaars, Gerard N.; Jacobs, Pauline; Timmer, C. J.; Paanakker, J.E.; Hal, Henk J.M. Van; Voortman, G.

doi:10.2165/00044011-199815010-00006

Cited by 79 publications

(73 citation statements)

References 13 publications

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“…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 .In human studies, the R(Ϫ)-enantiomer is preferentially conjugated to form a quaternary N-glucuronide directly, but the S(ϩ)-enantiomer is preferentially transformed to 8-hydroxymirtazapine, followed by glucuronide conjugation (Delbressine et al, 1998). In the antidepressant drug mianserin, which differs from mirtazapine in that a carbon 1 Abbreviations used are: 5-HT x , postsynaptic serotonin type 1, 2, or 3; HPLC, high performance liquid chromatography; NOE, nuclear Overhauser effect; DEP, direct exposure probe; EI, electron ionization; DEP, direct exposure probe; EI, electron ionization; CD, circular dichroism.…”

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confidence: 99%

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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mentioning

confidence: 99%

Biotransformation of Mirtazapine byCunninghamella Elegans

Moody¹,

Freeman²,

Fu³

et al. 2002

Drug Metab Dispos

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“…75,87 Demethylmirtazapine is the active metabolite, but its exposure in the human body is three times lower compared with the parent drug. 74 Low inhibitory effects of mirtazapine on major CYP isoenzymes were reported in vitro. 83,88 No significant interactions with the CYP2D6 substrates amitriptyline, clozapine, olanzapine, and risperidone were observed.…”

Section: Mirtazapinementioning

confidence: 99%

“…The most common adverse event with escitalopram was headache, and nausea with paroxetine. 74 Moreover, nausea, sweating, and obstipation were significantly less frequent compared with venlafaxine. 22,68 Cipriani et al reported better tolerability of escitalopram compared with duloxetine, paroxetine, reboxetine, sertraline, fluvoxamine, and venlafaxine.…”

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confidence: 96%

Getting the balance right: Established and emerging therapies for major depressive disorders

Perović

Jovanović²,

Miljković³

et al. 2010

NDT

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Major depressive disorder (MDD) is a common and serious illness of our times, associated with monoamine deficiency in the brain. Moreover, increased levels of cortisol, possibly caused by stress, may be related to depression. In the treatment of MDD, the use of older antidepressants such as monoamine oxidase inhibitors and tricyclic antidepressants is decreasing rapidly, mainly due to their adverse effect profiles. In contrast, the use of serotonin reuptake inhibitors and newer antidepressants, which have dual modes of action such as inhibition of the serotonin and noradrenaline or dopamine reuptake, is increasing. Novel antidepressants have additive modes of action such as agomelatine, a potent agonist of melatonin receptors. Drugs in development for treatment of MDD include triple reuptake inhibitors, dual-acting serotonin reuptake inhibitors and histamine antagonists, and many more. Newer antidepressants have similar efficacy and in general good tolerability profiles. Nevertheless, compliance with treatment for MDD is poor and may contribute to treatment failure. Despite the broad spectrum of available antidepressants, there are still at least 30% of depressive patients who do not benefit from treatment. Therefore, new approaches in drug development are necessary and, according to current research developments, the future of antidepressant treatment may be promising.

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“…2). The former metabolite has no pharmacological effect, while DMR has been estimated to contribute 5-10% of the total pharmacodynamic activity of the drug (Delbressine et al, 1998). Recently, MRZ has been tested in cats (Quimby et al, 2011), dogs (Giorgi and Yun, 2011) and horses (Rouini et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Mirtazapine in Veterinary Medicine a Pharmacological Rationale for its Application in Chronic Pain

Saleh¹

2012

American Journal of Animal and Veterinary Sciences

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Problem statement:Many recent studies have shown that antidepressant agents have analgesic effects in addition to their intended primary actions. The Tricyclic Antidepressants (TCAs) have been recognized as an effective first-line treatment of human neuropathic pain but unfortunately they display a wide range of side effects. Recent studies have shown that Selective Serotonin Reuptake Inhibitors (SSRI) also have potential analgesic effects, albeit of a lower potency compared with the TCAs. Despite this, there is a trend for their increased use, in place of TCAs, in the treatment of chronic pain. Mirtazapine, a SSRI has been recently investigated in the context of veterinary medicine. It has shown favourable pharmacokinetic profiles. Despite the fact that it has mainly been used for anorexia and as an antiemetic for veterinary patients thus far, it could be potentially useful for the treatment of a wide range of anxiety-related conditions and as an analgesic in chronic and cancerassociated pain, due to its effects on both the noradrenergic and serotonic system. Rationale for the use of mirtazapine in veterinary medicine is reviewed in light of previously published literature. Conclusion/Recommendations: Mirtazapine is proposed as a potential analgesic for use in a multidrug analgesic regime in the context of veterinary medicine. Further studies need to be performed before it is implemented in clinical practice however.

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Pharmacokinetics and Biotransformation of Mirtazapine in Human Volunteers

Cited by 79 publications

References 13 publications

Biotransformation of Mirtazapine byCunninghamella Elegans

Biotransformation of Mirtazapine byCunninghamella Elegans

Getting the balance right: Established and emerging therapies for major depressive disorders

Mirtazapine in Veterinary Medicine a Pharmacological Rationale for its Application in Chronic Pain

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