title: Pharmacokinetic considerations in the treatment of hypertension in risperidone-medicated patients - thinking of clinically relevant CYP2D6 interactions.
abstract: Treatment of arterial hypertension in patients with severe mental illnesses often results in polypharmacy, potentially leading to drug-drug interactions. The objective of the study was to analyse the in vivo inhibitory potential of two antihypertensive drugs, amlodipine and metoprolol on CYP2D6 catalysed 9-hydroxylation of risperidone (RIS).
  
  
  
  A therapeutic drug monitoring database with plasma concentrations of RIS and 9-hydroxyrisperidone (9-OH-RIS) of 1584 patients was analysed. Three groups were considered; a group of patients receiving RIS without a potentially cytochrome influencing co-medication (control group, R0, n=852), a group co-medicated with amlodipine (RA, n=27) and a group, co-medicated with metoprolol (RM, n=41). Plasma concentrations, concentration-to-dose ratios (C/Ds) of RIS, 9-OH-RIS and the active moiety (AM), as well as the metabolic ratios were computed and compared using the Kruskal-Wallis test, the Mann-Whitney U test and the Jonckheere-Terpstra test to determine the means and different patterns of distribution of plasma concentrations as well as the concentration-to-dose ratios.
  
  
  
  The median daily dosage of RIS did not differ between the groups (p=0.708). No differences were found in median plasma concentrations of RIS, 9-OH-RIS and AM. However, concentration-to-dose ratios for RIS, 9-OH-RIS and AM were significantly higher in the amlodipine group (p=0.025, p=0.048 and p=0.005). In the metoprolol group, the concentration-to-dose ratio for RIS was significantly higher than in the control group (p=0.017), while the C/D for 9-OH-RIS and AM was not.
  
  
  
  Our data show a potential pharmacokinetic interaction, most likely via CYP3A4 between amlodipine and RIS, reflected in significantly different C/Ds for RIS, 9-OH-RIS and AM. Although the interaction did not result in significantly higher plasma levels, changes in C/Ds and their distribution with regard to the median concentrations were observed.
authors.affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Aachen, Germany Jülich Aachen Research Alliance, Translational Brain Medicine, Jülich/Aachen, Germany mpaulzen@ukaachen.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Paulzen
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany Department of Pharmacology and Toxicology, University of Regensburg, Regensburg, Germany.
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Haen
authors.affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Aachen, Germany Jülich Aachen Research Alliance, Translational Brain Medicine, Jülich/Aachen, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Gründer
authors.affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Aachen, Germany Jülich Aachen Research Alliance, Translational Brain Medicine, Jülich/Aachen, Germany.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Lammertz
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Regensburg, Regensburg, Germany Department of Pharmacology and Toxicology, University of Regensburg, Regensburg, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Stegmann
authors.affiliation: School for Mental Health and Neuroscience, Maastricht University, Maastricht, the Netherlands.
authors.forename: Koen Rj
authors.initials: KR
authors.lastname: Schruers
authors.affiliation: University Hospital of Psychiatry, Bern, Switzerland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Walther
authors.affiliation: Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Aachen, Germany Jülich Aachen Research Alliance, Translational Brain Medicine, Jülich/Aachen, Germany University Hospital of Psychiatry, Bern, Switzerland.
authors.forename: Georgios
authors.initials: G
authors.lastname: Schoretsanitis
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017311:Amlodipine / Q000008:administration & dosage / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D016903:Drug Monitoring / Q000379:methods; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D008297:Male; D001523:Mental Disorders / Q000188:drug therapy; D008790:Metoprolol / Q000008:administration & dosage / Q000494:pharmacology; D008875:Middle Aged; D000068882:Paliperidone Palmitate / Q000493:pharmacokinetics; D012189:Retrospective Studies; D018967:Risperidone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000959:Antihypertensive Agents; D014150:Antipsychotic Agents; D017311:Amlodipine; D019389:Cytochrome P-450 CYP2D6; D008790:Metoprolol; D018967:Risperidone; D000068882:Paliperidone Palmitate
keywords: CYP2D6; Therapeutic drug monitoring; amlodipine; interaction; metoprolol; pharmacokinetics; risperidone