Relationship between plasma, atrial and ventricular perhexiline concentrations in humans

insights into factors affecting myocardial uptake

Nigel E. Drury, Giovanni Licari, Cher-Rin Chong, Neil J. Howell, Michael P. Frenneaux, John D. Horowitz, Domenico Pagano, Benedetta C. Sallustio*

*Corresponding author for this work

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

AimLittle 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.

MethodsBlood, 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.

ResultsAtrial biopsies were obtained from 94 patients and ventricular biopsies from 28 patients. The median plasma perhexiline concentration was within the therapeutic range at 0.24mgl(-1) (IQR 0.12-0.44), the median atrial concentration was 6.02mgkg(-1) (IQR 2.70-9.06) and median ventricular concentration was 10.0mgkg(-1) (IQR 5.76-13.1). Atrial (r(2) = 0.76) and ventricular (r(2) = 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 (r(2) = 0.83). Ventricular concentrations were directly correlated with plasma perhexiline concentration and length of therapy (r(2) = 0.84).

ConclusionsThis 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.

Original languageEnglish
Pages (from-to)789-795
Number of pages7
JournalBritish Journal of Clinical Pharmacology
Volume77
Issue number5
Early online date22 Apr 2014
DOIs
Publication statusPublished - May 2014

Keywords

  • drug uptake
  • myocardium
  • perhexiline
  • pharmacokinetics
  • antianginal agent
  • heart
  • drugs
  • inhibition
  • maleate
  • digoxin
  • angina
  • liver
  • trial

Cite this

Relationship between plasma, atrial and ventricular perhexiline concentrations in humans : insights into factors affecting myocardial uptake. / Drury, Nigel E.; Licari, Giovanni; Chong, Cher-Rin; Howell, Neil J.; Frenneaux, Michael P.; Horowitz, John D.; Pagano, Domenico; Sallustio, Benedetta C.

In: British Journal of Clinical Pharmacology, Vol. 77, No. 5, 05.2014, p. 789-795.

Research output: Contribution to journalArticle

Drury, NE, Licari, G, Chong, C-R, Howell, NJ, Frenneaux, MP, Horowitz, JD, Pagano, D & Sallustio, BC 2014, 'Relationship between plasma, atrial and ventricular perhexiline concentrations in humans: insights into factors affecting myocardial uptake', British Journal of Clinical Pharmacology, vol. 77, no. 5, pp. 789-795. https://doi.org/10.1111/bcp.12254
Drury, Nigel E. ; Licari, Giovanni ; Chong, Cher-Rin ; Howell, Neil J. ; Frenneaux, Michael P. ; Horowitz, John D. ; Pagano, Domenico ; Sallustio, Benedetta C. / Relationship between plasma, atrial and ventricular perhexiline concentrations in humans : insights into factors affecting myocardial uptake. In: British Journal of Clinical Pharmacology. 2014 ; Vol. 77, No. 5. pp. 789-795.
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abstract = "AimLittle 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.MethodsBlood, 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.ResultsAtrial biopsies were obtained from 94 patients and ventricular biopsies from 28 patients. The median plasma perhexiline concentration was within the therapeutic range at 0.24mgl(-1) (IQR 0.12-0.44), the median atrial concentration was 6.02mgkg(-1) (IQR 2.70-9.06) and median ventricular concentration was 10.0mgkg(-1) (IQR 5.76-13.1). Atrial (r(2) = 0.76) and ventricular (r(2) = 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 (r(2) = 0.83). Ventricular concentrations were directly correlated with plasma perhexiline concentration and length of therapy (r(2) = 0.84).ConclusionsThis 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.",
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author = "Drury, {Nigel E.} and Giovanni Licari and Cher-Rin Chong and Howell, {Neil J.} and Frenneaux, {Michael P.} and Horowitz, {John D.} and Domenico Pagano and Sallustio, {Benedetta C.}",
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T1 - Relationship between plasma, atrial and ventricular perhexiline concentrations in humans

T2 - insights into factors affecting myocardial uptake

AU - Drury, Nigel E.

AU - Licari, Giovanni

AU - Chong, Cher-Rin

AU - Howell, Neil J.

AU - Frenneaux, Michael P.

AU - Horowitz, John D.

AU - Pagano, Domenico

AU - Sallustio, Benedetta C.

N1 - Funded by British Heart Foundation. Grant Number: PG/06/044/20703 Wellcome Trust Queen Elizabeth Hospital Birmingham Charity Medical Research Council Programme Grant Queen Elizabeth Hospital Research Foundation/University of Adelaide Postgraduate Scholarship University of Adelaide Postgraduate Scholarship

PY - 2014/5

Y1 - 2014/5

N2 - AimLittle 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.MethodsBlood, 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.ResultsAtrial biopsies were obtained from 94 patients and ventricular biopsies from 28 patients. The median plasma perhexiline concentration was within the therapeutic range at 0.24mgl(-1) (IQR 0.12-0.44), the median atrial concentration was 6.02mgkg(-1) (IQR 2.70-9.06) and median ventricular concentration was 10.0mgkg(-1) (IQR 5.76-13.1). Atrial (r(2) = 0.76) and ventricular (r(2) = 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 (r(2) = 0.83). Ventricular concentrations were directly correlated with plasma perhexiline concentration and length of therapy (r(2) = 0.84).ConclusionsThis 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.

AB - AimLittle 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.MethodsBlood, 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.ResultsAtrial biopsies were obtained from 94 patients and ventricular biopsies from 28 patients. The median plasma perhexiline concentration was within the therapeutic range at 0.24mgl(-1) (IQR 0.12-0.44), the median atrial concentration was 6.02mgkg(-1) (IQR 2.70-9.06) and median ventricular concentration was 10.0mgkg(-1) (IQR 5.76-13.1). Atrial (r(2) = 0.76) and ventricular (r(2) = 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 (r(2) = 0.83). Ventricular concentrations were directly correlated with plasma perhexiline concentration and length of therapy (r(2) = 0.84).ConclusionsThis 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.

KW - drug uptake

KW - myocardium

KW - perhexiline

KW - pharmacokinetics

KW - antianginal agent

KW - heart

KW - drugs

KW - inhibition

KW - maleate

KW - digoxin

KW - angina

KW - liver

KW - trial

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DO - 10.1111/bcp.12254

M3 - Article

VL - 77

SP - 789

EP - 795

JO - British Journal of Clinical Pharmacology

JF - British Journal of Clinical Pharmacology

SN - 0306-5251

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