Paroxetine, a cytochrome P450 2D6 inhibitor, diminishes the stereoselective -demethylation and reduces the hypoalgesic effect of tramadol

Laugesen, Sune; Enggaard, Thomas P.; Pedersen, Robert Smith; Sindrup, Søren Hein; Brøsen, Kim

doi:10.1016/j.clpt.2004.11.002

Cited by 95 publications

(64 citation statements)

References 39 publications

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“…[8][9][10] Additionally, similar to our results in rats (Table 3), these human studies have shown that the AUCs of the M1 metabolites after single oral doses of T are nonstereoselective. 8,10 This was also true for steady-state data after multiple oral dosing of an immediate release formulation of T. 8 On the other hand, another study 13 investigating the pharmacokinetics of the enantiomers of T and M1 after multiple oral doses of a sustained release formulation of rac-T demonstrated stereoselectivity in the plasma concentrations of M1 in favor of the (À)-enantiomer [(À):(þ) plasma concentration ratios of 1.15 to 1.40]. Our data in rats suggest a stereoselective metabolism of T in the GI tract in favor of the (À)-enantiomer.…”

Section: Discussionsupporting

confidence: 90%

“…8,10,14,15 A very recent study 8 indicated that, whereas the area under the plasma concentration-time curves (AUCs) of M1 enantiomers were similar in extensive metabolizers, very little (þ)-M1 was generated in poor metabolizers. Overall, these studies indicate that the pharmacokinetics and pharmacodynamics of T are both stereoselective and complex, and their understanding in different patient populations and disease states requires measurement of the individual enantiomers of T and its active metabolite M1.…”

Section: Introductionmentioning

confidence: 97%

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Route‐dependent stereoselective pharmacokinetics of tramadol and its active O‐demethylated metabolite in rats

et al. 2006

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The effects of route of administration on the stereoselective pharmacokinetics of tramadol (T) and its active metabolite (M1) were studied in rats. A single 20 mg/kg dose of racemic T was administered through intravenous, intraperitoneal, or oral route to different groups of rats, and blood and urine samples were collected. Samples were analyzed using chiral chromatography, and pharmacokinetic parameters (mean +/- SD) were estimated by noncompartmental methods. Following intravenous injection, there was no stereoselectivity in the pharmacokinetics of T. Both enantiomers showed clearance values (62.5 +/- 27.2 and 64.4 +/- 39.0 ml/min/kg for (+)- and (-)-T, respectively) that were equal or higher than the reported liver blood flow in rats. Similar to T, the area under the plasma concentration-time curves (AUCs) of M1 did not exhibit stereoselectivity after intravenous administration of the parent drug. However, the systemic availability of (+)-T was significantly (P < 0.05) higher than that of its antipode following intraperitoneal (0.527 +/- 0.240 vs. 0.373 +/- 0.189) and oral (0.307 +/- 0.136 vs. 0.159 +/- 0.115) administrations. The AUC of the M1 enantiomers, on the other hand, remained mostly nonstereoselective regardless of the route of administration. Pharmacokinetic analysis indicated that the stereoselectivity in the pharmacokinetics of oral T is due to stereoselective first pass metabolism in the liver and, possibly, in the gastrointestinal tract. The direction and extent of stereoselectivity in the pharmacokinetics of T and M1 in rats were in agreement with those previously reported in humans, suggesting that the rat may be a suitable model for enantioselective studies of T pharmacokinetics.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 97%

Route‐dependent stereoselective pharmacokinetics of tramadol and its active O‐demethylated metabolite in rats

et al. 2006

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“…Although in that article the authors identified both racemic T and racemic M1 as active components, an interaction pd model combining the effects of T and M1 could not be established. T is still a matter of active research, for example, it has been suggested as a new probe for cytochrome P450 2D6 phenotyping (11) and in a recent study (12), the analgesic effects of T were decreased after coadministration of paroxetine (a cytochrome P450 2D6 inhibitor) confirming again that M1 is an important element of T activity (13). To date a mechanistic pk/pd model addressing the different contribution of the enantiomers of T and the active metabolite M1 has not been established yet.…”

Section: Introductionmentioning

confidence: 99%

Semi-mechanistic Pharmacokinetic/Pharmacodynamic Modelling of the Antinociceptive Response in the Presence of Competitive Antagonism: The Interaction Between Tramadol and its Active Metabolite on μ-Opioid Agonism and Monoamine Reuptake Inhibition, in the Rat

Beier¹,

Garrido

Christoph

et al. 2007

Pharm Res

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“…Parts of this work were previously presented as a poster as follows: Germain JM, Patroneva A, Connolly SM, Fatato P, Paul J, Isler JA, Burczynski M, GuicoPabia C, and Nichols AI (2007) An assessment of drug-drug interactions: the effects of desvenlafaxine succinate and duloxetine on the pharmacokinetics of the CYP2D6 probe desipramine in healthy subjects. , 1997;Laugesen et al, 2005), the antiarrhythmic amiodarone (Fukumoto et al, 2006), the analgesic codeine (Zanger et al, 2004), and the cyclooxygenase-2 inhibitor celecoxib (Werner et al, 2003). It is important, therefore, that physicians are aware of the potential for clinically relevant interactions when prescribing antidepressants.…”

mentioning

confidence: 99%

“…For example, paroxetine and fluoxetine strongly inhibit CYP2D6 (K i of 2.0 and 3.0 M, respectively), whereas citalopram and sertraline have been shown to be moderate or weak inhibitors (K i of 19 and 22.7 M, respectively) (Skjelbo and Brosen, 1992;von Moltke et al, 1995;Preskorn, 2003;Preskorn et al, 2007a). CYP2D6 is responsible for the metabolism of drugs (and activation of prodrugs) commonly used to treat various medical conditions; some examples include the antiestrogen tamoxifen (Stearns et al, 2003), the atypical opioid tram-adol (Mason and Blackburn, 1997;Laugesen et al, 2005), the antiarrhythmic amiodarone (Fukumoto et al, 2006), the analgesic codeine (Zanger et al, 2004), and the cyclooxygenase-2 inhibitor celecoxib (Werner et al, 2003). It is important, therefore, that physicians are aware of the potential for clinically relevant interactions when prescribing antidepressants.…”

mentioning

confidence: 99%

An Assessment of Drug-Drug Interactions: The Effect of Desvenlafaxine and Duloxetine on the Pharmacokinetics of the CYP2D6 Probe Desipramine in Healthy Subjects

Patroneva¹,

Connolly²,

Fatato³

et al. 2008

Drug Metabolism and Disposition

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ABSTRACT:A number of antidepressants inhibit the activity of the cytochrome P450 2D6 enzyme system, which can lead to drug-drug interactions. Based on its metabolic profile, desvenlafaxine, administered as desvenlafaxine succinate, a new serotonin-norepinephrine reuptake inhibitor, is not expected to have an impact on activity of CYP2D6. This single-center, randomized, open-label, four-period, crossover study was undertaken to evaluate the effect of multiple doses of desvenlafaxine (100 mg/day, twice the recommended therapeutic dose for major depressive disorder in the United States) and duloxetine (30 mg b.i.d.) on the pharmacokinetics (PK) of a single dose of desipramine (50 mg). A single dose of desipramine was given first to assess its PK. Desvenlafaxine or duloxetine was then administered, in a crossover design, so that steady-state levels were achieved; a single dose of desipramine was then coadministered. The geometric least-square mean ratios (coadministration versus desipramine alone) for area under the plasma concentration versus time curve (AUC) and peak plasma concentrations (C max ) of desipramine and 2-hydroxydesipramine were compared using analysis of variance. Relative to desipramine alone, increases in AUC and C max of desipramine associated with duloxetine administration (122 and 63%, respectively) were significantly greater than those associated with desvenlafaxine (22 and 19%, respectively; P < 0.001). Duloxetine coadministered with desipramine was also associated with a decrease in 2-hydroxydesipramine C max that was significant compared with the small increase seen with desvenlafaxine and desipramine (؊24 versus 9%; P < 0.001); the difference between changes in 2-hydroxydesipramine AUC did not reach statistical significance (P ‫؍‬ 0.054). Overall, desvenlafaxine had a minimal impact on the PK of desipramine compared with duloxetine, suggesting a lower risk for CYP2D6-mediated drug interactions.Concomitant use of a drug that affects the activity of the same cytochrome P450 (P450) enzyme system responsible for biotransformation of another drug can lead to significant elevations in plasma concentration and potentially important drug-drug interactions (Preskorn and Flockhart, 2004). Such interactions may be associated with poor tolerability or increased risk for toxicity. In addition, for drugs requiring biotransformation via P450 enzymes from an inactive/less active parent compound to a pharmacologically active metabolite, drug interactions may manifest as a reduction in efficacy (Stearns et al., 2003;Preskorn and Flockhart, 2004;Preskorn and Werder, 2006). Drug interactions have an impact on clinical care and may create the need for dose adjustments, consideration of different therapeutic options, or other management strategies.Several antidepressants are known to inhibit CYP2D6 activity (Zanger et al., 2004). The selective serotonin reuptake inhibitors are associated with varying degrees of CYP2D6 inhibition. For example, paroxetine and fluoxetine strongly inhibit CYP2D6 (K i of 2.0 and 3.0 ...

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Paroxetine, a cytochrome P450 2D6 inhibitor, diminishes the stereoselective -demethylation and reduces the hypoalgesic effect of tramadol

Cited by 95 publications

References 39 publications

Route‐dependent stereoselective pharmacokinetics of tramadol and its active O‐demethylated metabolite in rats

Route‐dependent stereoselective pharmacokinetics of tramadol and its active O‐demethylated metabolite in rats

Semi-mechanistic Pharmacokinetic/Pharmacodynamic Modelling of the Antinociceptive Response in the Presence of Competitive Antagonism: The Interaction Between Tramadol and its Active Metabolite on μ-Opioid Agonism and Monoamine Reuptake Inhibition, in the Rat

An Assessment of Drug-Drug Interactions: The Effect of Desvenlafaxine and Duloxetine on the Pharmacokinetics of the CYP2D6 Probe Desipramine in Healthy Subjects

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