title: Relationship between plasma, atrial and ventricular perhexiline concentrations in humans: insights into factors affecting myocardial uptake.
abstract: OBJECTIVE
  Little is known regarding the steady-state uptake of drugs into the human myocardium. Perhexiline is a prophylactic anti-anginal drug which is increasingly also used in the treatment of heart failure and hypertrophic cardiomyopathy. We explored the relationship between plasma perhexiline concentrations and its uptake into the myocardium.
  
  
  METHODS
  Blood, right atrium ± left ventricle biopsies were obtained from patients treated with perhexiline for a median of 8.5 days before undergoing coronary surgery in the perhexiline arm of a randomized controlled trial. Perhexiline concentrations in plasma and heart tissue were determined by HPLC.
  
  
  RESULTS
  Atrial biopsies were obtained from 94 patients and ventricular biopsies from 28 patients. The median plasma perhexiline concentration was within the therapeutic range at 0.24 mg l⁻¹ (IQR 0.12-0.44), the median atrial concentration was 6.02  mg kg⁻¹ (IQR 2.70-9.06) and median ventricular concentration was 10.0 mg kg⁻¹ (IQR 5.76-13.1). Atrial (r² = 0.76) and ventricular (r² = 0.73) perhexiline concentrations were closely and directly correlated with plasma concentrations (both P < 0.001). The median atrial : plasma ratio was 21.5 (IQR 18.1-27.1), ventricular : plasma ratio was 34.9 (IQR 24.5-55.2) and ventricular : atrial ratio was 1.67 (IQR 1.39-2.22). Using multiple regression, the best model for predicting steady-state atrial concentration included plasma perhexiline, heart rate and age (r² = 0.83). Ventricular concentrations were directly correlated with plasma perhexiline concentration and length of therapy (r² = 0.84).
  
  
  CONCLUSIONS
  This study demonstrates that plasma perhexiline concentrations are predictive of myocardial drug concentrations, a major determinant of drug effect. However, net myocardial perhexiline uptake is significantly modulated by patient age, potentially via alteration of myocardial:extracardiac drug uptake.
authors.affiliation: Departments of Clinical Pharmacology and Cardiology, Basil Hetzel Institute, The Queen Elizabeth Hospital, Woodville, SA, Australia; The Discipline of Surgery, University of Adelaide, Adelaide, SA, Australia; Department of Cardiothoracic Surgery, Queen Elizabeth Hospital, Birmingham, UK.
authors.forename: Nigel E
authors.initials: NE
authors.lastname: Drury
authors.forename: Giovanni
authors.initials: G
authors.lastname: Licari
authors.forename: Cher-Rin
authors.initials: CR
authors.lastname: Chong
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Howell
authors.forename: Michael P
authors.initials: MP
authors.lastname: Frenneaux
authors.forename: John D
authors.initials: JD
authors.lastname: Horowitz
authors.forename: Domenico
authors.initials: D
authors.lastname: Pagano
authors.forename: Benedetta C
authors.initials: BC
authors.lastname: Sallustio
mesh_terms: D000367:Age Factors; D000368:Aged; D001706:Biopsy; D004311:Double-Blind Method; D006801:Humans; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D010480:Perhexiline / Q000493:pharmacokinetics*; D011446:Prospective Studies
chemical_list: D010480:Perhexiline
keywords: drug uptake; myocardium; perhexiline; pharmacokinetics