title: Stereoselective handling of perhexiline: implications regarding accumulation within the human myocardium.
abstract: OBJECTIVE
  Perhexiline is a prophylactic anti-ischaemic agent with weak calcium antagonist effect which has been increasingly utilised in the management of refractory angina. The metabolic clearance of perhexiline is modulated by CYP2D6 metaboliser status and stereoselectivity. The current study sought to (1) determine whether the acute accumulation of perhexiline in the myocardium is stereoselective and (2) investigate the relationship between duration of short-term therapy and the potential stereoselective effects of perhexiline within myocardium.
  
  
  METHODS
  Patients (n = 129) from the active arm of a randomised controlled trial of preoperative perhexiline in cardiac surgery were treated with oral perhexiline for a median of 9 days. Correlates of atrial and ventricular concentrations of enantiomers were sought via univariate followed by multivariate analyses.
  
  
  RESULTS
  Myocardial uptake of both (+) and (-) perhexiline was greater in ventricles than in atria, and there was more rapid clearance of (-) than (+) perhexiline. The main determinants of atrial uptake of both (+) and (-) perhexiline were the plasma concentrations [(+) perhexiline: β = -0.256, p = 0.015; (-) perhexiline: β = -0.347, p = 0.001] and patients' age [(+) perhexiline: β = 0.300, p = 0.004; (-) perhexiline: β = 0.288, p = 0.005]. Atrial uptake of (+) enantiomer also varied directly with duration of therapy (β = 0.228, p = 0.025), while atrial uptake of (-) perhexiline varied inversely with simultaneous heart rate (β = -0.240, p = 0.015).
  
  
  CONCLUSIONS
  (1) Uptake of both perhexiline enantiomers into atrium is greater with advanced age and displays evidence of both saturability and minor stereoselectivity. (2) Atrial uptake of (-) perhexiline may selectively modulate heart rate reduction.
authors.affiliation: Cardiology and Clinical Pharmacology Departments, Basil Hetzel Institute, Queen Elizabeth Hospital, Woodville South, South Australia, Australia.|Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Cher-Rin
authors.initials: CR
authors.lastname: Chong
authors.affiliation: Cardiology and Clinical Pharmacology Departments, Basil Hetzel Institute, Queen Elizabeth Hospital, Woodville South, South Australia, Australia.|Department of Cardiothoracic Surgery, Queen Elizabeth Hospital Birmingham, Birmingham, UK.|School of Clinical & Experimental Medicine, University of Birmingham, Birmingham, UK.
authors.forename: Nigel E
authors.initials: NE
authors.lastname: Drury
authors.affiliation: Cardiology and Clinical Pharmacology Departments, Basil Hetzel Institute, Queen Elizabeth Hospital, Woodville South, South Australia, Australia.|Pharmacology, University of Adelaide, Adelaide, South Australia.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Licari
authors.affiliation: Norwich Medical School, University of East Anglia, Norwich, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Frenneaux
authors.affiliation: Cardiology and Clinical Pharmacology Departments, Basil Hetzel Institute, Queen Elizabeth Hospital, Woodville South, South Australia, Australia.|Medicine, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: John D
authors.initials: JD
authors.lastname: Horowitz
authors.affiliation: Department of Cardiothoracic Surgery, Queen Elizabeth Hospital Birmingham, Birmingham, UK.|School of Clinical & Experimental Medicine, University of Birmingham, Birmingham, UK.
authors.forename: Domenico
authors.initials: D
authors.lastname: Pagano
authors.affiliation: Cardiology and Clinical Pharmacology Departments, Basil Hetzel Institute, Queen Elizabeth Hospital, Woodville South, South Australia, Australia. benedetta.sallustio@health.sa.gov.au.|Pharmacology, University of Adelaide, Adelaide, South Australia. benedetta.sallustio@health.sa.gov.au.
authors.forename: Benedetta C
authors.initials: BC
authors.lastname: Sallustio
mesh_terms: D000284:Administration, Oral; D000368:Aged; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D006325:Heart Atria / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism*; D010480:Perhexiline / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D013237:Stereoisomerism; D014018:Tissue Distribution
chemical_list: D002317:Cardiovascular Agents; D010480:Perhexiline
keywords: Drug uptake; Metabolism; Perhexiline; Pharmacokinetics; Stereoselectivity