The role of cytochrome P4502D6 in the metabolism of paroxetine by human liver microsomes.

Bloomer, J. C.; Woods, F. R.; Haddock, R. E.; Lennard,; Tucker, GT

doi:10.1111/j.1365-2125.1992.tb04082.x

Cited by 125 publications

(44 citation statements)

References 8 publications

(8 reference statements)

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“…This removal of the carbon at the methylenedioxy position is catalyzed by cytochrome P4502D6 (CYP2D6) (Bloomer et al, 1992;Crewe et al, 1992), yielding a catechol that is subsequently both methylated and conjugated (Tulloch and Johnson, 1992). The metabolites of paroxetine are considered to be pharmacologically inactive (Kaye et al, 1989).…”

Section: Introductionmentioning

confidence: 99%

Multiple Dose Pharmacokinetics of Paroxetine in Children and Adolescents with Major Depressive Disorder or Obsessive–Compulsive Disorder

Findling

Nucci

Piergies³

et al. 2005

Neuropsychopharmacol

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The current study examined the pharmacokinetics (PK), safety, and tolerability of paroxetine after repeated multiple oral dosing in children and adolescents with major depressive or obsessive-compulsive disorder. In this 6-week, open-label, repeat dose, dose-rising study, 62 patients (27 children and 35 adolescents) were treated with paroxetine 10 mg/day for the first 2 weeks of the study, 20 mg/day for the next 2 weeks, and 30 mg/day for the final 2 weeks. Pharmacokinetic sampling and safety assessments occurred at baseline and subsequently on the final treatment day of each dosing level. Between-patient variability in PK was pronounced at the 10 mg dose level, but markedly reduced at higher doses. A supra-proportional increase in plasma concentrations with increasing dose was evident in both age groups. Data for C max and AUC (0À24) indicated that, at each dose level, paroxetine steady-state systemic exposure was higher in children than in adolescents. The differences between age groups, however, diminished with each increasing dose, and were virtually abolished when differences in weight among different age groups were considered. Stepwise regression analysis indicated that both oral clearance and volume of distribution were highly dependent on paroxetine dose, cytochrome P4502D6 genotype, and weight (po0.0001), but not age or sex. Paroxetine was generally safe and well tolerated in both age groups, with the most frequently observed adverse events being largely consistent with those observed in prior paroxetine studies of adult psychiatric patients. Certain gastrointestinal and behavioral activation events (aggressive reaction and nervousness) were reported more frequently in the youngest age group.

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Section: Introductionmentioning

confidence: 99%

Multiple Dose Pharmacokinetics of Paroxetine in Children and Adolescents with Major Depressive Disorder or Obsessive–Compulsive Disorder

Findling

Nucci

Piergies³

et al. 2005

Neuropsychopharmacol

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“…The receptor binding profile and effects on neurotransmitter uptake of ODV are strated that the SSRIs were approximately 10-300 fold more potent CYP2D6 inhibitors (K i values, 0.065-1.8 mm) than venlafaxine (K i , 20.0 mm [3]). Of the SSRIs, only and inhibitor of CYP2D6 [4,5]. While among the SSRIs Research Institute, Toronto, Canada.…”

Section: Introduction N-demethylation As Well As a Combination Of N-mentioning

confidence: 99%

Venlafaxine: in vitro inhibition of CYP2D6 dependent imipramine and desipramine metabolism; comparative studies with selected SSRIs, and effects on human hepatic CYP3A4, CYP2C9 and CYP1A2

Ball

Ahern

Scatina

et al. 1997

Brit J Clinical Pharma

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Aims In order to anticipate drug-interactions of potential clinical significance the ability of the novel antidepressant, venlafaxine, to inhibit CYP2D6 dependent imipramine and desipramine 2-hydroxylation was investigated in human liver microsomes. The data obtained were compared with the selective serotonin re-uptake inhibitors, fluoxetine, sertraline, fluvoxamine and paroxetine. Venlafaxine's potential to inhibit several other major P450s was also studied (CYP3A4, CYP2D6, CYP1A2). Methods K i values for venlafaxine, paroxetine, fluoxetine, fluvoxamine and sertraline as inhibitors of imipramine and desipramine 2-hydroxylation were determined from Dixon plots of control and inhibited rate data in human hepatic microsomal incubations. The inhibitory effect of imipramine and desipramine on liver microsomal CYP2D6 dependent venlafaxine O-demethylation was determined similarly. Venlafaxine's IC 50 values for CYP3A4, CYP1A2 CYP2C9 were determined based on inhibition of probe substrate activities (testosterone 6b-hydroxylation, ethoxyresorufin O-dealkylase and tolbutamide 4-hydroxylation, respectively). Results Fluoxetine, paroxetine, and fluvoxamine were potent inhibitors of imipramine 2-hydroxylase activity (K i values of 1.6±0.8, 3.2±0.8 and 8.0±4.3 mm, respectively; mean±s.d., n=3), while sertraline was less inhibitory (K i of 24.7±8.9 mm). Fluoxetine also markedly inhibited desipramine 2-hydroxylation with a K i of 1.3±0.5 mm. Venlafaxine was less potent an inhibitor of imipramine 2-hydroxylation (K i of 41.0±9.5 mm) than the SSRIs that were studied. Imipramine and desipramine gave marked inhibition of CYP2D6 dependent venlafaxine O-demethylase activity (K i values of 3.9±1.7 and 1.7±0.9 mm, respectively). Venlafaxine did not inhibit ethoxyresorufin O-dealkylase (CYP1A2), tolbutamide 4-hydroxylase (CYP2C9) or testosterone 6b-hydroxylase (CYP3A4) activities at concentrations of up to 1 mm. Conclusions It is concluded that venlafaxine has a low potential to inhibit the metabolism of substrates for CYP2D6 such as imipramine and desipramine compared with several of the most widely used SSRIs, as well as the metabolism of substrates for several of the other major human hepatic P450s.

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“…Paroxetine is metabolized by CYP2D6 via demethylenation of the methylenedioxy group, yielding a catechol metabolite and formic acid (Haddock et al, 1989;Bloomer et al, 1992). Paroxetine inhibits CYP2D6 activity at IC 50 concentrations ranging from 150 nM to 2.0 M, depending on the substrate (Crewe et al, 1992;von Moltke et al, 1995;Fogelman et al, 1999).…”

mentioning

confidence: 99%

“…Paroxetine is a selective serotonin reuptake inhibitor with nonlinear kinetics that is both a substrate for and an inhibitor of CYP2D6 Belpaire et al, 1998;Otton et al, 1996;Bloomer et al, 1992;Sindrup et al, 1992a,b). Paroxetine is metabolized by CYP2D6 via demethylenation of the methylenedioxy group, yielding a catechol metabolite and formic acid (Haddock et al, 1989;Bloomer et al, 1992).…”

mentioning

confidence: 99%

Apparent Mechanism-based Inhibition of Human CYP2D6 in Vitro by Paroxetine: Comparison with Fluoxetine and Quinidine

Bertelsen

Venkatakrishnan²,

Moltke³

et al. 2003

Drug Metab Dispos

250

174

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Paroxetine, a selective serotonin reuptake inhibitor, is a potent inhibitor of cytochrome P450 2D6 (CYP2D6) activity, but the mechanism of inhibition is not established. To determine whether preincubation affects the inhibition of human liver microsomal dextromethorphan demethylation activity by paroxetine, we used a twostep incubation scheme in which all of the enzyme assay components, minus substrate, are preincubated with paroxetine. The kinetic parameters of inhibition were also estimated by varying the time of preincubation as well as the concentration of inhibitor.

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The role of cytochrome P4502D6 in the metabolism of paroxetine by human liver microsomes.

Cited by 125 publications

References 8 publications

Multiple Dose Pharmacokinetics of Paroxetine in Children and Adolescents with Major Depressive Disorder or Obsessive–Compulsive Disorder

Multiple Dose Pharmacokinetics of Paroxetine in Children and Adolescents with Major Depressive Disorder or Obsessive–Compulsive Disorder

Venlafaxine: in vitro inhibition of CYP2D6 dependent imipramine and desipramine metabolism; comparative studies with selected SSRIs, and effects on human hepatic CYP3A4, CYP2C9 and CYP1A2

Apparent Mechanism-based Inhibition of Human CYP2D6 in Vitro by Paroxetine: Comparison with Fluoxetine and Quinidine

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