title: Phenotypic differences in nebivolol metabolism and bioavailability in healthy volunteers.
abstract: BACKGROUND
  Nebivolol, a third-generation β-blocker, is subject to extensive first-pass metabolism and produces active β-blocking hydroxylated metabolites, like 4-OH-nebivolol. It is primarily a substrate of CYP2D6, a metabolic pathway that is under polymorphic genetic regulation. The objective of this study was to assess the metabolizer phenotype and to evaluate the interphenotype bioavailability and metabolism of nebivolol.
  
  
  METHODS
  Forty-three healthy volunteers were included in this open-label, non-randomized clinical trial and each volunteer received a single dose of 5 mg nebivolol. Non-compartmental pharmacokinetic analysis was performed to determine the pharmacokinetic parameters of nebivolol and its active metabolite. The phenotypic distribution was assessed based on the AUC (aria under the curve) metabolic ratio of nebivolol/4-OH-nebivolol and statistical analysis. An interphenotype comparison of nebivolol metabolism and bioavailability was performed based on the pharmacokinetic parameters of nebivolol and its active metabolite.
  
  
  RESULTS
  Nebivolol/4-OH-nebivolol AUC metabolic ratios were not characterized by a standard normal distribution. The unique distribution emphasized the existence of two groups and the 43 healthy volunteers were classified as follows: poor metabolizers (PMs)=3, extensive metabolizers (EMs)=40. The phenotype had a marked impact on nebivolol metabolism. The exposure to nebivolol was 15-fold greater for PMs in comparison to EMs.
  
  
  CONCLUSIONS
  40 EMs and 3 PMs were differentiated by using the pharmacokinetic parameters of nebivolol and its active metabolite. The study highlighted the existence of interphenotype differences regarding nebivolol metabolism and bioavailability.
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmacy, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
authors.forename: Corina
authors.initials: C
authors.lastname: Briciu
authors.affiliation: Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
authors.forename: Maria
authors.initials: M
authors.lastname: Neag
authors.affiliation: Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
authors.forename: Dana
authors.initials: D
authors.lastname: Muntean
authors.affiliation: Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
authors.forename: Corina
authors.initials: C
authors.lastname: Bocsan
authors.affiliation: Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
authors.forename: Anca
authors.initials: A
authors.lastname: Buzoianu
authors.affiliation: Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
authors.forename: Oana
authors.initials: O
authors.lastname: Antonescu
authors.affiliation: Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Gheldiu
authors.affiliation: Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
authors.forename: Marcela
authors.initials: M
authors.lastname: Achim
authors.affiliation: Department of Clinical Pharmacy, Faculty of Pharmacy, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
authors.forename: Adina
authors.initials: A
authors.lastname: Popa
authors.affiliation: Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Pharmacy, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.
authors.forename: Laurian
authors.initials: L
authors.lastname: Vlase
keywords: CYP2D6; nebivolol; pharmacokinetics; phenotype