Pharmacokinetics of Desipramine Coadministered With Sertraline or Fluoxetine

Preskorn, Sheldon; Alderman, Jeffrey; Chung, Mun Su; Harrison, Wilma; Messig, Michael; Harris, Stuart

doi:10.1097/00004714-199404000-00002

Cited by 119 publications

(66 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The relatively short plasma half-lives of venlafaxine and ODMvenlafaxine ( 5 and 11 h, respectively, us 1 to 11 days [34] for the other SSRIs tested here) suggest that the duration of any inhibition will be less. These arguments were experimentally tested recently by Preskorn et al [9] in comparing CYP2D6 inhibition during the recommended dosing regimens of sertraline and fluoxetine. They demonstrated that sertraline's combination of lower affinity for CYP2D6, shorter half-life and lower plasma concentrations resulted in significantly less inhibition of CYP2D6-catalyzed desipramine oxidation in vivo and a shorter duration of the pharmacokinetic interaction.…”

Section: Venlafaxinr N-demethylationmentioning

confidence: 99%

“…The Ki values of sertraline and its N-demethylated metabolite for CYP2D6 are approximately six times higher than the corresponding values for fluoxetine and norfluoxetine [S]. Compared with fluoxetine, the lower inherent affinity for CYP2D6 together with the lower effective plasma concentrations of sertraline and N-desmethylsertaline results in considerably less CYP2D6 inhibition after sertraline dosing [9]. Two other SSRI agents, fluvoxamine and citalop-150 S. I/.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Venlafaxine oxidation in vitro is catalysed by CYP2D6

Otton

Ball

Cheung

et al. 1996

Brit J Clinical Pharma

217

151

View full text Add to dashboard Cite

1 Several selective 5-HT reuptake inhibitors (SSRIs) are inhibitors of the genetically polymorphic drug metabolizing enzyme, CYP2D6. We studied the interaction of venlafaxine, a new SSRI, with CYP2D6 in human liver microsomes. 2 Venlafaxine was a less potent inhibitor of this enzyme activity in vitro than other SSRIs tested. The average apparent K i values determined using CY P2D6-dependent dextromethorphan 0-demethylation were: 33, 52 and 22 PM for rac-venlafaxine, R( +)-venlafaxine and S (-)-venlafaxine, respectively, us 0.065 to 1.8 p~ for paroxetine, fluoxetine, norfluoxetine, fluvoxamine and sertraline. 3 Microsomes from human livers ( n = 3 ) and from yeast transformed with an expression plasmid containing human CYP2D6 cDNA catalyzed the 0-demethylation of venlafaxine, which is the major metabolic pathway in uiuo. Intrinsic metabolic clearance values ( Vmax/Km) indicated that S( -)-venlafaxine was cleared preferentially via this pathway. 4 In microsomes from CYP2D6-deficient livers (n = 2), Vmax/Km of O-demethylation of venlafaxine was one to two orders of magnitude lower and was similar to the rate of N-demethylation. 5 Studies with chemical probes which preferentially inhibit P450 isoforms suggested that CYP3A3/4 is involved in venlafaxine N-demethylation. 6 These in vitro findings predict phenotypic differences in the kinetics of venlafaxine in vivo, although the clinical importance of this is unclear as 0-demethylvenlafaxine is pharmacologically similar to the parent drug. The findings also predict relatively limited pharmacokinetic interaction between venlafaxine and other CYP2D6 substrates.

show abstract

Section: Venlafaxinr N-demethylationmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Venlafaxine oxidation in vitro is catalysed by CYP2D6

Otton

Ball

Cheung

et al. 1996

Brit J Clinical Pharma

217

151

View full text Add to dashboard Cite

show abstract

“…Desipramine is primarily eliminated through CYP2D6-mediated metabolism by forming 2-hydroxydesipramine (Bjornsson et al, 2003); approximately 40% of a single, oral dose of desipramine is recovered as 2-hydroxydesipramine in the urine (Spina et al, 1996). A 50-mg dose of desipramine has been established as an appropriate substrate to test CYP2D6 inhibition (Preskorn et al, 1994;Preskorn and Flockhart, 2004). Duloxetine, a CYP2D6 inhibitor with an in vitro K i of 4.5 M (data on file), was included in this study as a positive control because it is a moderate inhibitor.…”

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 Metab Dispos

View full text Add to dashboard Cite

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 ...

show abstract

“…Desconocemos si una dosis mayor de 20 mg de fluoxetina podría haber mejorado a un mayor número de pacientes. Es probable que en los pacientes que recibieron primero fluoxetina y luego desipramina las concentraciones plasmáticas de la desipramina hayan sido mayores por al menos 3 semanas 29,30 , por inhibición de la citocromo P450 subunidad 2D6 de la fluoxetina y su metabolito la norfluoxetina. En concordancia, eventos adversos como bochornos e insomnio se presentaron más cuando los pacientes fueron cambiados de fluoxetina a desipramina.…”

Section: Figura 2 Puntajes Promedio En La Escala De Impresión Clínicunclassified

Respuesta a antidepresivos serotoninérgicos y noradrenérgicos: estudio cruzado con fluoxetina y desipramina en pacientes con un primer episodio depresivo mayor

Barquera

2017

GMM

View full text Add to dashboard Cite

Pharmacokinetics of Desipramine Coadministered With Sertraline or Fluoxetine

Cited by 119 publications

References 0 publications

Venlafaxine oxidation in vitro is catalysed by CYP2D6

Venlafaxine oxidation in vitro is catalysed by CYP2D6

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

Respuesta a antidepresivos serotoninérgicos y noradrenérgicos: estudio cruzado con fluoxetina y desipramina en pacientes con un primer episodio depresivo mayor

Contact Info

Product

Resources

About