title: Effect of CYP2D6 polymorphisms on the pharmacokinetics of propafenone and its two main metabolites.
abstract: OBJECTIVE
  Propafenone (PPF) is an antiarrhythmic drug, metabolized mainly by CYP2D6 to 5-hydroxypropafenone (5OH-PPF) and by CYP3A4 to norpropafenone (NOR-PPF). CYP2D6 shows a high degree of genetic polymorphism which is associated with diminished antiarrhythmic efficacy or cardiac seizures/cardiotoxicity. This study aimed to investigate the effect of the CYP2D6 polymorphism on the pharmacokinetics of PPF and its two main metabolites. The usefulness of PPF/5OH-PPF ratio for CYP2D6 phenotyping in healthy adults was also evaluated.
  
  
  METHODS
  Twelve healthy volunteers, 3 poor metabolizers (PM), 2 intermediate metabolizers (IM) and seven extensive metabolizers (EM) received an oral dose of PPF. Concentrations of PPF and its metabolites were analyzed in serum samples over 27h.
  
  
  RESULTS
  The PPF/5OH-PPF ratio distinguished EMs from PMs, but not from IMs. In PMs, the mean transit time (MTT) values were almost the same for PPF and NOR-PPF and much higher than those of EMs and IMs. 5OH-PPF was not detected in EMs. Mean MTT values of 5OH-PPF and NOR-PPF in IMs were 5.27- and 1.52-fold higher than those of EMs.
  
  
  CONCLUSIONS
  A single time point serum PPF-MR approach is a useful tool to identify PMs. CYP2D6 polymorphism significantly affects the pharmacokinetics of PPF and its two metabolites.
authors.affiliation: Biopharmaceutics and pharmacokinetics division, department of pharmaceutics, faculty of pharmacy, Tehran university of medical sciences, P.O. Box 14155-6451, Tehran, Iran.
authors.forename: Mohammad-Reza
authors.initials: MR
authors.lastname: Rouini
authors.affiliation: Biopharmaceutics and pharmacokinetics division, department of pharmaceutics, faculty of pharmacy, Tehran university of medical sciences, P.O. Box 14155-6451, Tehran, Iran; Department of pharmaceutics, pharmaceutical sciences branch, Islamic Azad university (IAUPS), Tehran 193956466, Iran. Electronic address: afsharme@sina.tums.ac.ir.
authors.forename: Minoo
authors.initials: M
authors.lastname: Afshar
mesh_terms: D000328:Adult; D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000493:pharmacokinetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011405:Propafenone / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000889:Anti-Arrhythmia Agents; D011405:Propafenone; C044307:5-hydroxypropafenone; D019389:Cytochrome P-450 CYP2D6
keywords: CYP2D6 polymorphism; Hydroxypropafenone; Hydroxypropafénone; Norpropafenone; Norpropafénone; Pharmacocinétique; Pharmacokinetics; Polymorphisme du CYP2D6; Propafenone; Propafénone