title: The dopaminergic stabilizer pridopidine is to a major extent N-depropylated by CYP2D6 in humans.
abstract: OBJECTIVE
  The influence of the cytochrome P450 enzyme CYP2D6 in the metabolism of the novel dopaminergic stabilizer pridopidine was investigated in healthy Swedish Caucasians.
  
  
  METHODS
  Six extensive metabolizers (EM) and six poor metabolizers (PM) of debrisoquine were given a single oral dose of pridopidine (EM, 50 mg; PM, 25 mg).
  
  
  RESULTS
  The mean total plasma clearance of pridopidine was 541 and 138 mL/min in EM and PM, respectively (p = 0.003), and was slightly higher in PM than the mean renal plasma clearance (105 mL/min; p = 0.11). The mean plasma area under the time-concentration curve between time zero and 32 h (AUC(0-32 h)) of the N-depropyl metabolite ACR30 was higher in EM than in PM (1,377 vs. 61 nmol h/mL, respectively; p < 0.001). The urinary excretion of pridopidine + ACR30 was high in both EM (85 %) and PM (78 %). The dose-adjusted peak concentration (C(max)) was not statistically different in EM and PM; consequently, the oral absorption of pridopidine was close to complete.
  
  
  CONCLUSIONS
  Following a single dose of pridopidine, the drug is N-depropylated by CYP2D6 in EM, while in PM the most important elimination pathway is renal glomerular filtration. Results of studies examining the effects of multiple repeat dosing suggest that the CYP2D6 enzyme is at least partly inactivated by pridopidine.
authors.affiliation: Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Stockholm, Sweden. anders.hellden@karolinska.se
authors.forename: A
authors.initials: A
authors.lastname: Helldén
authors.forename: G
authors.initials: G
authors.lastname: Panagiotidis
authors.forename: P
authors.initials: P
authors.lastname: Johansson
authors.forename: N
authors.initials: N
authors.lastname: Waters
authors.forename: S
authors.initials: S
authors.lastname: Waters
authors.forename: J
authors.initials: J
authors.lastname: Tedroff
authors.forename: L
authors.initials: L
authors.lastname: Bertilsson
mesh_terms: D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D001711:Biotransformation; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D003640:Dealkylation; D018492:Dopamine Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics; D005919:Glomerular Filtration Rate; D006207:Half-Life; D006801:Humans; D007408:Intestinal Absorption; D007668:Kidney / Q000378:metabolism; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010641:Phenotype; D010880:Piperidines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D013548:Sweden; D044465:White People; D055815:Young Adult
chemical_list: D065690:Cytochrome P-450 CYP2D6 Inhibitors; D018492:Dopamine Antagonists; D004791:Enzyme Inhibitors; D010880:Piperidines; D019389:Cytochrome P-450 CYP2D6; C483720:pridopidine