Impact of CYP2D6 Functional Allelic Variations on Phenoconversion and Drug-Drug Interactions

Clin Pharmacol Ther. 2018 Jul;104(1):148-157. doi: 10.1002/cpt.889. Epub 2017 Nov 6.

Abstract

We investigated whether CYP2D6 extensive metabolizers carrying a nonfunctional allele are at higher risk of phenoconversion to poor metabolizers in the presence of CYP2D6 inhibitors. Seventeen homozygous carriers of two fully-functional alleles and 17 heterozygous carriers of one fully-functional and one nonfunctional allele participated in this trial. Dextromethorphan 5 mg and tramadol 10 mg were given at each of the three study sessions. CYP2D6 was inhibited by duloxetine 60 mg (session 2) and paroxetine 20 mg (session 3). A higher rate of phenoconversion to intermediate metabolizers with duloxetine (71% vs. 25%, P = 0.009) and to poor metabolizers with paroxetine (94% vs. 56%, P = 0.011) was observed in heterozygous than homozygous extensive metabolizers. The magnitude of drug-drug interaction between dextromethorphan and paroxetine was higher in homozygous than in heterozygous subjects (14.6 vs. 8.5, P < 0.028). Our study suggests that genetic extensive metabolizers may not represent a homogenous population and that available genetic data should be considered when addressing drug-drug interactions in clinical practice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Alleles
  • Analgesics, Opioid / metabolism
  • Analgesics, Opioid / pharmacokinetics
  • Antitussive Agents / metabolism
  • Antitussive Agents / pharmacokinetics
  • Cytochrome P-450 CYP2D6 / drug effects*
  • Cytochrome P-450 CYP2D6 / genetics
  • Cytochrome P-450 CYP2D6 / metabolism
  • Cytochrome P-450 CYP2D6 Inhibitors / pharmacology*
  • Dextromethorphan / metabolism
  • Dextromethorphan / pharmacokinetics
  • Drug Interactions
  • Duloxetine Hydrochloride / pharmacology*
  • Female
  • Genotype
  • Heterozygote
  • Homozygote
  • Humans
  • Male
  • Paroxetine / pharmacology*
  • Pharmacogenomic Variants
  • Phenotype
  • Tramadol / metabolism
  • Tramadol / pharmacokinetics
  • Young Adult

Substances

  • Analgesics, Opioid
  • Antitussive Agents
  • Cytochrome P-450 CYP2D6 Inhibitors
  • Tramadol
  • Paroxetine
  • Dextromethorphan
  • Duloxetine Hydrochloride
  • Cytochrome P-450 CYP2D6
pFad - Phonifier reborn

Pfad - The Proxy pFad of © 2024 Garber Painting. All rights reserved.

Note: This service is not intended for secure transactions such as banking, social media, email, or purchasing. Use at your own risk. We assume no liability whatsoever for broken pages.


Alternative Proxies:

Alternative Proxy

pFad Proxy

pFad v3 Proxy

pFad v4 Proxy