Review of the pharmacokinetics, pharmacogenetics, and drug interaction potential of antidepressants: Focus on venlafaxine

Ereshefsky, Larry; Dugan, Daniel J.

doi:10.1002/1520-6394(2000)12:1+<30::aid-da4>3.0.co;2-g

Cited by 85 publications

(64 citation statements)

References 65 publications

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“…There is no evidence that venlafaxine or its metabolites inhibit 2C19 [40], so this is unlikely to account for the prolonged plasma elimination half-life in these two patients. Neither was unwell or had a history of renal or hepatic disease.…”

Section: Figurementioning

confidence: 92%

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Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity

Hackett

Dawson

Whyte

et al. 2003

Brit J Clinical Pharma

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Aims To investigate the spectrum of toxicity of moclobemide overdose, the occurrence of serotonin toxicity, and to estimate toxicokinetic parameters. Methods All moclobemide overdoses presenting over a 10-year period to the Hunter Area Toxicology Service were reviewed. Clinical features, complications, length of stay (LOS) and intensive care (ICU) admission rate were extracted from a standardized, prospectively collected database. Comparisons were made between moclobemide alone and moclobemide with a serotonergic coingestant poisoning. Serotonin toxicity was defined by a combination of Sternbach's criteria and a clinical toxicologist's diagnosis. In five patients serial moclobemide concentrations were measured. Time to maximal plasma concentration ( T max ), peak plasma concentration ( C max ) and terminal elimination half-lives were estimated. Results Of 106 included patients, 33 ingested moclobemide alone, 21 ingested moclobemide with another serotonergic agent (in some cases in therapeutic doses) and 52 ingested moclobemide with a nonserotonergic agent. Eleven (55%) of 21 patients coingesting a serotonergic drug developed serotonin toxicity, which was significantly more than one (3%) of 33 moclobemide-alone overdoses (odds ratio 35, 95% confidence inteval 4, 307; P < 0.0001). In six of these 21 cases severe serotonin toxicity developed with temperature > 38.5 ∞ C and muscle rigidity requiring intubation and paralysis. The 21 patients had a significantly increased LOS (34 h) compared with moclobemide alone overdoses (12 h) ( P < 0.0001) and a significantly increased ICU admission rate of 57% vs. 3% ( P < 0.0001). Time to peak plasma concentration was delayed in two patients where prepeak samples were obtained. C max increased slightly with dose, but all three patients ingesting ≥ 6 g vomited or had charcoal. The mean elimination half-life of moclobemide in the five patients in whom serial moclobemide concentrations were measured was 6.3 h and elimination was first order in all cases. There was no evidence of a dose-dependent increase in half-life. Conclusions The effects of moclobemide alone in overdose are minor, even with massive ingestions. However, moclobemide overdose in combination with a serotonergic agent (even in normal therapeutic doses) can cause severe serotonin toxicity. The elimination half-life is prolonged by two to four times in overdose, compared with that found in healthy volunteers given therapeutic doses. This may be a result of wide interindividual variation in overall elimination, also seen with therapeutic doses, but appears not to be due to saturation of normal elimination pathways.

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Section: Figurementioning

confidence: 92%

“…None was taking moclobemide therapeutically, so the increased half-lives were not a result of multiple dosing. All three coingested antidepressants (Table 3), but this is unlikely to account for the longer half-lives because only fluvoxamine is a potent inhibitor of 2C19 [40,41].…”

Section: Figurementioning

confidence: 99%

Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity

Hackett

Dawson

Whyte

et al. 2003

Brit J Clinical Pharma

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“…156 The drug is widely distributed in the body, with low protein binding and a high volume of distribution (see Table 2). 118,119 Following oral absorption, venlafaxine undergoes extensive first-pass hepatic metabolism, where conversion to the active metabolite, desvenlafaxine, occurs via demethylation. 157 This reaction is mediated by CYP2D6.…”

Section: 152mentioning

confidence: 99%

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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“…It is the major active metabolite of venlafaxine (VEN) and has an antidepressant activity profile similar to that of VEN but with a better tolerability and a much longer half-life (Muth et al, 1986;Rudorfer and Potter, 1997;Ereshefsky and Dugan, 2000). Unexpectedly, ODV failed to be approved in EU (Anonymous, 2009), owing to an unfavorable risk/benefit profile associated with the treatment of depression and hot flushes.…”

Section: Introductionmentioning

confidence: 99%

A Phenolic Ester of <i>O</i>-Desmethylvenlafaxine (ODV) Improves Uptake of ODV into the Brain

Zhang¹,

Yang²,

Zhao³

et al. 2016

American Journal of Biochemistry and Biotechnology

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In this study, the in vitro stabilities of a promising ODesmethylvenlafaxine (ODV) phenolic ester prodrug O-19 in aqueous solution, rat whole blood and rat liver microsomes were investigated. In addition, the in vivo drug metabolites were determined using LC-TOFMS-IDA-MS/MS. O-19 exhibits high stabilities at any pH encountered in the gastrointestinal tract, its half live (t 1/2 ) spans the range 5.0±0.18 d ~ 686±29.5 d. However, O-19 experiences rapid enzymatic hydrolysis in rat whole blood (t 1/2 = 3.6±0.53 min) and rat liver microsomes (t 1/2 = 9.5±1.53 min). The metabolic profile of O-19 is similar to that of ODV. Besides ODV itself, five metabolites are identified in rat urine (M 1~M5 ) and faeces (M 1 , M 4 ), no obvious toxic metabolite is detected.

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Review of the pharmacokinetics, pharmacogenetics, and drug interaction potential of antidepressants: Focus on venlafaxine

Cited by 85 publications

References 65 publications

Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity

Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity

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

A Phenolic Ester of <i>O</i>-Desmethylvenlafaxine (ODV) Improves Uptake of ODV into the Brain

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