CYP2D6 inhibition by fluoxetine, paroxetine, sertraline, and venlafaxine in a crossover study: Intraindividual variability and plasma concentration correlations

C. L. Alfaro, Yui-wing F Lam, J. Simpson, L. Ereshefsky

Research output: Contribution to journalArticle

107 Citations (Scopus)

Abstract

The authors report the CYP2D6 inhibitory effects of fluoxetine, paroxetine, sertraline, and venlafaxine in an open-label, multiple-dose, crossover design. Twelve CYP2D6 extensive metabolizers were phenotyped, using the dextromethorphan/dextrorphan (DM/DX) urinary ratio, before and after administration of fluoxetine 60 mg (loading dose strategy), paroxetine 20 mg, sertraline 100 mg, and venlafaxine 150 mg. Paroxetine, sertraline, and venlafaxine sequences were randomized with 2-week washouts between treatments; fluoxetine was the last antidepressant (AD) administered. Comparing within groups, baseline DM/DX ratios (0.017) were significantly lower than DM/DX ratios after treatment (DM/DX(AD)) with fluoxetine (0.313, p < 0.0001) and paroxetine (0.601, p < 0.0001) but not for sertraline (0.026, p = 0.066) or venlafaxine (0.023, p = 0.485). Between groups, DM/DX(AD) ratios were significantly higher for fluoxetine and paroxetine compared to sertraline and venlafaxine. No differences between DM/DX(AD) ratios were found for fluoxetine and paroxetine although more subjects phenocopied to PM status after receiving the latter (42% vs. 83%; χ2 = 4.44, p = 0.049, df = 1). Similarly, no differences between DM/DX(AD) ratios were found for sertraline and venlafaxine. Of note, the DM/DX(AD) for 1 subject was much lower after treatment with paroxetine (0.058) compared to fluoxetine (0.490), while another subject exhibited a much lower ratio after treatment with fluoxetine (0.095) compared to paroxetine (0.397). Significant correlations between AD plasma concentration and DM/DX(AD) were found for paroxetine (r2 = 0.404, p = 0.026) and sertraline (r2 = 0.64, p = 0.002) but not fluoxetine or venlafaxine. In addition, DM/DX(AD) correlated with baseline isoenzyme activity for paroxetine, sertraline, and venlafaxine groups. These results demonstrate the potent, but variable, CYP2D6 inhibition of fluoxetine and paroxetine compared to sertraline and venlafaxine. CYP2D6 inhibition may be related, in part, to dose, plasma concentration, and baseline isoenzyme activity, and these correlations merit further investigation. (C) 2000 the American College of Clinical Pharmacology.

Original languageEnglish (US)
Pages (from-to)58-66
Number of pages9
JournalJournal of Clinical Pharmacology
Volume40
Issue number1
StatePublished - 2000

Fingerprint

Dextrorphan
Sertraline
Cytochrome P-450 CYP2D6
Paroxetine
Dextromethorphan
Fluoxetine
Cross-Over Studies
Antidepressive Agents
Isoenzymes
Venlafaxine Hydrochloride

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

Cite this

@article{ab451847293a47abaf49e5b7ffb04b9e,
title = "CYP2D6 inhibition by fluoxetine, paroxetine, sertraline, and venlafaxine in a crossover study: Intraindividual variability and plasma concentration correlations",
abstract = "The authors report the CYP2D6 inhibitory effects of fluoxetine, paroxetine, sertraline, and venlafaxine in an open-label, multiple-dose, crossover design. Twelve CYP2D6 extensive metabolizers were phenotyped, using the dextromethorphan/dextrorphan (DM/DX) urinary ratio, before and after administration of fluoxetine 60 mg (loading dose strategy), paroxetine 20 mg, sertraline 100 mg, and venlafaxine 150 mg. Paroxetine, sertraline, and venlafaxine sequences were randomized with 2-week washouts between treatments; fluoxetine was the last antidepressant (AD) administered. Comparing within groups, baseline DM/DX ratios (0.017) were significantly lower than DM/DX ratios after treatment (DM/DX(AD)) with fluoxetine (0.313, p < 0.0001) and paroxetine (0.601, p < 0.0001) but not for sertraline (0.026, p = 0.066) or venlafaxine (0.023, p = 0.485). Between groups, DM/DX(AD) ratios were significantly higher for fluoxetine and paroxetine compared to sertraline and venlafaxine. No differences between DM/DX(AD) ratios were found for fluoxetine and paroxetine although more subjects phenocopied to PM status after receiving the latter (42{\%} vs. 83{\%}; χ2 = 4.44, p = 0.049, df = 1). Similarly, no differences between DM/DX(AD) ratios were found for sertraline and venlafaxine. Of note, the DM/DX(AD) for 1 subject was much lower after treatment with paroxetine (0.058) compared to fluoxetine (0.490), while another subject exhibited a much lower ratio after treatment with fluoxetine (0.095) compared to paroxetine (0.397). Significant correlations between AD plasma concentration and DM/DX(AD) were found for paroxetine (r2 = 0.404, p = 0.026) and sertraline (r2 = 0.64, p = 0.002) but not fluoxetine or venlafaxine. In addition, DM/DX(AD) correlated with baseline isoenzyme activity for paroxetine, sertraline, and venlafaxine groups. These results demonstrate the potent, but variable, CYP2D6 inhibition of fluoxetine and paroxetine compared to sertraline and venlafaxine. CYP2D6 inhibition may be related, in part, to dose, plasma concentration, and baseline isoenzyme activity, and these correlations merit further investigation. (C) 2000 the American College of Clinical Pharmacology.",
author = "Alfaro, {C. L.} and Lam, {Yui-wing F} and J. Simpson and L. Ereshefsky",
year = "2000",
language = "English (US)",
volume = "40",
pages = "58--66",
journal = "Journal of Clinical Pharmacology",
issn = "0091-2700",
publisher = "SAGE Publications Inc.",
number = "1",

}

TY - JOUR

T1 - CYP2D6 inhibition by fluoxetine, paroxetine, sertraline, and venlafaxine in a crossover study

T2 - Intraindividual variability and plasma concentration correlations

AU - Alfaro, C. L.

AU - Lam, Yui-wing F

AU - Simpson, J.

AU - Ereshefsky, L.

PY - 2000

Y1 - 2000

N2 - The authors report the CYP2D6 inhibitory effects of fluoxetine, paroxetine, sertraline, and venlafaxine in an open-label, multiple-dose, crossover design. Twelve CYP2D6 extensive metabolizers were phenotyped, using the dextromethorphan/dextrorphan (DM/DX) urinary ratio, before and after administration of fluoxetine 60 mg (loading dose strategy), paroxetine 20 mg, sertraline 100 mg, and venlafaxine 150 mg. Paroxetine, sertraline, and venlafaxine sequences were randomized with 2-week washouts between treatments; fluoxetine was the last antidepressant (AD) administered. Comparing within groups, baseline DM/DX ratios (0.017) were significantly lower than DM/DX ratios after treatment (DM/DX(AD)) with fluoxetine (0.313, p < 0.0001) and paroxetine (0.601, p < 0.0001) but not for sertraline (0.026, p = 0.066) or venlafaxine (0.023, p = 0.485). Between groups, DM/DX(AD) ratios were significantly higher for fluoxetine and paroxetine compared to sertraline and venlafaxine. No differences between DM/DX(AD) ratios were found for fluoxetine and paroxetine although more subjects phenocopied to PM status after receiving the latter (42% vs. 83%; χ2 = 4.44, p = 0.049, df = 1). Similarly, no differences between DM/DX(AD) ratios were found for sertraline and venlafaxine. Of note, the DM/DX(AD) for 1 subject was much lower after treatment with paroxetine (0.058) compared to fluoxetine (0.490), while another subject exhibited a much lower ratio after treatment with fluoxetine (0.095) compared to paroxetine (0.397). Significant correlations between AD plasma concentration and DM/DX(AD) were found for paroxetine (r2 = 0.404, p = 0.026) and sertraline (r2 = 0.64, p = 0.002) but not fluoxetine or venlafaxine. In addition, DM/DX(AD) correlated with baseline isoenzyme activity for paroxetine, sertraline, and venlafaxine groups. These results demonstrate the potent, but variable, CYP2D6 inhibition of fluoxetine and paroxetine compared to sertraline and venlafaxine. CYP2D6 inhibition may be related, in part, to dose, plasma concentration, and baseline isoenzyme activity, and these correlations merit further investigation. (C) 2000 the American College of Clinical Pharmacology.

AB - The authors report the CYP2D6 inhibitory effects of fluoxetine, paroxetine, sertraline, and venlafaxine in an open-label, multiple-dose, crossover design. Twelve CYP2D6 extensive metabolizers were phenotyped, using the dextromethorphan/dextrorphan (DM/DX) urinary ratio, before and after administration of fluoxetine 60 mg (loading dose strategy), paroxetine 20 mg, sertraline 100 mg, and venlafaxine 150 mg. Paroxetine, sertraline, and venlafaxine sequences were randomized with 2-week washouts between treatments; fluoxetine was the last antidepressant (AD) administered. Comparing within groups, baseline DM/DX ratios (0.017) were significantly lower than DM/DX ratios after treatment (DM/DX(AD)) with fluoxetine (0.313, p < 0.0001) and paroxetine (0.601, p < 0.0001) but not for sertraline (0.026, p = 0.066) or venlafaxine (0.023, p = 0.485). Between groups, DM/DX(AD) ratios were significantly higher for fluoxetine and paroxetine compared to sertraline and venlafaxine. No differences between DM/DX(AD) ratios were found for fluoxetine and paroxetine although more subjects phenocopied to PM status after receiving the latter (42% vs. 83%; χ2 = 4.44, p = 0.049, df = 1). Similarly, no differences between DM/DX(AD) ratios were found for sertraline and venlafaxine. Of note, the DM/DX(AD) for 1 subject was much lower after treatment with paroxetine (0.058) compared to fluoxetine (0.490), while another subject exhibited a much lower ratio after treatment with fluoxetine (0.095) compared to paroxetine (0.397). Significant correlations between AD plasma concentration and DM/DX(AD) were found for paroxetine (r2 = 0.404, p = 0.026) and sertraline (r2 = 0.64, p = 0.002) but not fluoxetine or venlafaxine. In addition, DM/DX(AD) correlated with baseline isoenzyme activity for paroxetine, sertraline, and venlafaxine groups. These results demonstrate the potent, but variable, CYP2D6 inhibition of fluoxetine and paroxetine compared to sertraline and venlafaxine. CYP2D6 inhibition may be related, in part, to dose, plasma concentration, and baseline isoenzyme activity, and these correlations merit further investigation. (C) 2000 the American College of Clinical Pharmacology.

UR - http://www.scopus.com/inward/record.url?scp=0033710657&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033710657&partnerID=8YFLogxK

M3 - Article

C2 - 10631623

AN - SCOPUS:0033710657

VL - 40

SP - 58

EP - 66

JO - Journal of Clinical Pharmacology

JF - Journal of Clinical Pharmacology

SN - 0091-2700

IS - 1

ER -