The effect of selective serotonin re‐uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes.

Crewe, H.K.; Lennard,; Tucker, GT; Woods, F. R.; Haddock, R. E.

doi:10.1111/j.1365-2125.1992.tb04134.x

Cited by 427 publications

(176 citation statements)

References 12 publications

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“…As a result, these women may take selective serotonin reuptake inhibitors (SSRIs) to ameliorate hot flashes but there are potential pharmacological consequences to this strategy. Some of the SSRIs are metabolitically altered by the CYP2D6 enzyme product [39]. It is therefore possible to envision a drug interaction whereby SSRIs block the metabolic activation of tamoxifen.…”

Section: Tamoxifen the First Sermmentioning

confidence: 99%

“…The SSRIs are twice as effective as the "placebo" effect at reducing menopausal symptoms in randomized clinical trials [138][139][140], so there is naturally an increased usage of SSRIs with long-term tamoxifen treatment to maintain compliance. Unfortunately, the metabolism of tamoxifen to hydroxylated metabolites [141][142][143] and the metabolism of SSRIs [39,[144][145][146][147] both occur via the CYP2D6 gene product. Indeed Stearns and coworkers [97] showed that the SSRI inhibitor paroxetine reduced the levels of endoxifen during adjuvant tamoxifen therapy and endoxifen levels decrease by 64% in women with wild type CYP2D6 enzyme.…”

Section: Tamoxifen Metabolism Todaymentioning

confidence: 99%

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New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

2007

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The metabolism of tamoxifen is being redefined in the light of several important pharmacological observations. Recent studies have identified 4-hydroxy N-desmethyl tamoxifen (endoxifen) as an important metabolite of tamoxifen necessary for antitumor actions. The metabolite is formed through the enzymatic product of CYP2D6 which also interacts with specific selective serotonin reuptake inhibitors (SSRIs) used to prevent the hot flashes observed in up to 45% of patients taking tamoxifen. Additionally, the finding that enzyme variants of CYP2D6 do not promote the metabolism of tamoxifen to endoxifen means that significant numbers of women might not receive optimal benefit from tamoxifen treatment. Clearly these are particularly important issues not only for breast cancer treatment but also for selecting premenopausal women, at high risk for breast cancer, as candidates for chemoprevention using tamoxifen.

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Section: Tamoxifen the First Sermmentioning

confidence: 99%

Section: Tamoxifen Metabolism Todaymentioning

confidence: 99%

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

2007

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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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“…SSRIs such as fluoxetine [3], paroxetine [4] and sertraline [5] are extensively metabolized by the liver, whereas citalopram is partially eliminated unchanged by the kidneys [1,6]. Although the enzyme(s) responsible for the metabolism of SSRIs has not yet been fully characterized, in vitro human liver microsomal studies have suggested that an isoform of cytochrome P450, CYP2D6, is involved in the metabolism of SSRIs [7][8][9], being in agreement with an in vivo human panel study [10].…”

Section: Introductionmentioning

confidence: 99%

The effects of selective serotonin reuptake inhibitors and their metabolites on S‐mephenytoin 4'‐hydroxylase activity in human liver microsomes.

Kobayashi

Yamamoto

Chiba

et al. 1995

Brit J Clinical Pharma

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The inhibitory effects of four selective serotonin reuptake inhibitors (SSRIs), fluoxetine, sertraline, paroxetine and citalopram, and three metabolites (norfluoxetine, demethylcitalopram and didemethylcitalopram), on S-mephenytoin 4'-hydroxylation activities in human liver microsomes were studied. The 4'-hydroxylation of S-mephenytoin, a representative substrate toward CYP2C19, was competitively inhibited by all the SSRIs and their metabolites studied. The mean Ki values of fluoxetine, norfluoxetine, sertraline, paroxetine, citalopram, demethylcitalopram and didemethylcitalopram were 5.2, 1.1, 2.0, 7.5, 87.3, 55.8 and 7.7 gIM, respectively. The findings suggest that some SSRIs and their metabolites with a low Ki value (e.g., fluoxetine, norfluoxetine) may reduce the clearance of drugs metabolized by this isoform of P450, thereby resulting in a possible drug-drug interaction, when administered simultaneously. In addition, SSRIs and their metabolites examined herein may be substrates toward CYP2C19.

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The effect of selective serotonin re‐uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes.

Cited by 427 publications

References 12 publications

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer

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

The effects of selective serotonin reuptake inhibitors and their metabolites on S‐mephenytoin 4'‐hydroxylase activity in human liver microsomes.

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