Two separate dose-dependent effects of paroxetine: mydriasis and inhibition of tramadol’s O-demethylation via CYP2D6

Nielsen, Anette Green; Pedersen, Robert Smith; Noehr-Jensen, Lene; Damkier, Per; Brøsen, Kim

doi:10.1007/s00228-010-0803-8

Cited by 18 publications

(16 citation statements)

References 37 publications

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“…Furthermore, a single 20-mg dose of paroxetine increases the metabolic ratio of (+)-tramadol .4-fold, consistent with almost 80% inhibition of CYP2D6 (Nielsen et al, 2010). However, it should be noted that, as paroxetine is a mechanism-based inhibitor of CYP2D6, which can reduce its own clearance due to a time-dependent autoinhibitory effect (Bertelsen et al, 2003;Sawamura et al, 2004), its CYP2D6-inhibiting effect may increase further during prolonged use.…”

Section: Discussionmentioning

confidence: 62%

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Paroxetine Markedly Increases Plasma Concentrations of Ophthalmic Timolol; CYP2D6 Inhibitors May Increase the Risk of Cardiovascular Adverse Effects of 0.5% Timolol Eye Drops

et al. 2014

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Although ophthalmic timolol is generally well tolerated, a significant fraction of topically administered timolol can be systemically absorbed. We investigated the effect of the strong CYP2D6 inhibitor paroxetine on the pharmacokinetics of timolol after ophthalmic administration. In a four-phase crossover study, 12 healthy volunteers ingested either paroxetine (20 mg) or placebo daily for 3 days. In phases 1-2, timolol 0.1% gel, and in phases 3-4, timolol 0.5% drops were administered to both eyes. Paroxetine increased the plasma concentrations of timolol with both timolol formulations to a similar degree. The geometric mean ratio (95% confidence interval) of timolol peak concentration was 1.53-fold (1.23-1.91) with 0.1% timolol and 1.49-fold (0.94-2.36) with 0.5% timolol, and that of timolol area under the plasma concentration-time curve (AUC) from time 0 to 12 hours was 1.61-fold (1.26-to 2.06-fold) and 1.78-fold (1.21-2.62), respectively. During paroxetine administration, six subjects on 0.5% timolol drops, but none on 0.1% timolol gel, had plasma timolol concentrations exceeding 0.7 ng/ml, which can cause systemic adverse effects in patients at risk. There was a positive correlation between the AUC from time 0 to 13 hours of paroxetine and the placebo phase AUC from time 0 to infinity of timolol after timolol 0.5% drops (P < 0.05), and a nonsignificant trend after timolol 0.1% gel, consistent with the role of CYP2D6 in the metabolism of both agents. In the orthostatic test, heart rate immediately after upright standing was significantly lower (P < 0.05) during the paroxetine phase than during the placebo phase at 1 and 3 hours after 0.5% timolol dosing. In conclusion, paroxetine and other CYP2D6 inhibitors can have a clinically important interaction with ophthalmic timolol, particularly when patients are using 0.5% timolol formulations.

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Section: Discussionmentioning

confidence: 62%

“…Thus, our short treatment may underestimate the extent of interaction, particularly in patients with ultra-rapid CYP2D6 genotype or reduced kidney function. Furthermore, the CYP2D6 inhibitory effect of paroxetine is dose-dependent (Sawamura et al, 2004;Nielsen et al, 2010). Thus, the interaction of …”

Section: Discussionmentioning

confidence: 99%

Paroxetine Markedly Increases Plasma Concentrations of Ophthalmic Timolol; CYP2D6 Inhibitors May Increase the Risk of Cardiovascular Adverse Effects of 0.5% Timolol Eye Drops

et al. 2014

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“…If violence, as a side effect of an SSRI, is linked to the presence in the blood of a relevant quantity of the serotonin reuptake inhibitor [25] Sometimes the intent defense is unsuccessful, because an accused's "own culpability" is taken as the starting point in law. Intent is then assumed on the basis of culpa in causa.…”

Section: The Importance Of the Concentration Of Paroxetinementioning

confidence: 99%

Aspects of Causality: A Verdict Inquiry of a Case with SSRI Use

Brouwers¹,

Loonen²,

Nielen³

et al. 2014

JHS

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Sometimes more than one expert advises the court. They use different notional frameworks in doing so, and may report different opinions about the case they examined. In this case, the authors discuss the relation between the use of a SSRI (serotonin reuptake inhibitor) and a fatal tragedy in a family where the mother was accused of killing her husband and daughter a few days after use of the SSRI. No fewer than seven experts were heard (four behavioral experts, one behavioral toxicologist, one pharmacist and one pharmacologist) at the ensuing trial, and various possible diagnoses were dealt with in the experts' reports and at trial. More attention must be paid to the mentally debilitating influence of SSRI medication on certain psychological functions shortly after its intake. Although a mono-causal relationship between that influence and the accused's intention is necessary to exculpate the accused from guilt, the authors believe that a singular connection is never happened in the case.

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“…)-M1 is the active l-opioid receptor agonist, while (? )-tramadol is an inhibitor of the 5-HT re-uptake and (-)-tramadol inhibits norepinephrine re-uptake [1][2][3][4][5]. Since M1 has significant l-opioid agonist activity, tramadol drug metabolism and its variability is also of pharmacodynamic relevance.…”

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confidence: 98%

“…We hereby want to make the point that the final phenotypic concentration (PK) or effect (PD) indeed in part depends on individual pharmacogenetic profile, but that other issues like age-related metabolic activity or (renal) elimination clearance also further contribute to the interindividual variability observed [3][4][5].…”

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confidence: 99%

Mechanism based medicine in infancy: complex interplay between developmental pharmacology and pharmacogenetics

Allegaert

2011

Int J Clin Pharm

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Introduction of the available knowledge on pharmacogenetics very likely is one of the tools to close the gap between 'population' focused evidence based and 'individual' mechanism based medicine. However, besides pharmacogenetics, other covariates like age, renal function and/or co-medication should also be considered simultaneously when aiming for a 'tailored' pharmacotherapy. To illustrate this, we further extended the tramadol example used by Wilffert et al. to illustrate the complex interplay between developmental pharmacology and pharmacogenetics.

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Two separate dose-dependent effects of paroxetine: mydriasis and inhibition of tramadol’s O-demethylation via CYP2D6

Abstract: Paroxetine is a dose-dependent dilator of the pupil and as expected a dose-dependent inhibitor of (+)-tramadol's O-demethylation.

Cited by 18 publications

References 37 publications

Paroxetine Markedly Increases Plasma Concentrations of Ophthalmic Timolol; CYP2D6 Inhibitors May Increase the Risk of Cardiovascular Adverse Effects of 0.5% Timolol Eye Drops

Paroxetine Markedly Increases Plasma Concentrations of Ophthalmic Timolol; CYP2D6 Inhibitors May Increase the Risk of Cardiovascular Adverse Effects of 0.5% Timolol Eye Drops

Aspects of Causality: A Verdict Inquiry of a Case with SSRI Use

Mechanism based medicine in infancy: complex interplay between developmental pharmacology and pharmacogenetics

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