The interactions of Propafenone and its enantiomers with the major human forms of cytochrome P450 in terms of inhibition and metabolic rates
type: CreativeWork
description: Propafenone is a class 1C antiarrhythmic drug used for the treatment of ventricular arrhythmias. Propafenone is a chiral compound which is normally administered as the racemate. The use of racemate therapy can be problematic as variability in both the pharmacodynamic and pharmacokinetic properties of the separate enantiomeric forms of the drug can exist. Propafenone enantiomers have been shown to have similar pharmacological properties, but studies are limited with regards to their disposition and interaction with drug metabolising enzymes. The aim of the study conducted here was to investigate the interaction of racaemic propafenone with the major cytochrome P450 isoforms (CYP2D6, CYP1A2, CYP3A4 and CYP2C19) to determine any stereospecific differences which may exist. This was conducted by measuring the in vitro metabolism of propafenone (racemate and enatiomers) and by developing CYP inhibition screens which could prove to be useful in providing information of potential drug interactions. In addition, stereospecific binding to human albumin was measured to investigate whether any enantiomeric differences in unbound drug exist. For the inhibition studies propafenone (racemate and enatiomers) was incubated in 96 well plates with separate CYP isoforms in the presence of a NADPH regenerating system. CYP activity was monitored using the following fluorogenic substrates: CYP2C19/ CYP1A2 – CEC; CYP2D6 – AMMC; CYP3A4 - BFC. IC50 values were calculated and compared to those of control inhibitors (CYP2C19 – Tranycylpromine; CYP2D6 – Quinidine; CYP3A4 – Ketoconazole ; CYP1A2 - Furafylline). In vitro metabolism was conducted using human liver microsomes incubated with propafenone (racemate and enatiomers) and the degree of metabolism measured using hplc analysis. Protein binding was estimated for propafenone (racemate and enatiomers) by a chromatographic method utilising a chiral HSA column. Inhibition studies showed that the lowest IC50 values were obtained when propafenone …
abstract: Propafenone is a class 1C antiarrhythmic drug used for the treatment of ventricular arrhythmias. Propafenone is a chiral compound which is normally administered as the racemate. The use of racemate therapy can be problematic as variability in both the pharmacodynamic and pharmacokinetic properties of the separate enantiomeric forms of the drug can exist. Propafenone enantiomers have been shown to have similar pharmacological properties, but studies are limited with regards to their disposition and interaction with drug metabolising enzymes. The aim of the study conducted here was to investigate the interaction of racaemic propafenone with the major cytochrome P450 isoforms (CYP2D6, CYP1A2, CYP3A4 and CYP2C19) to determine any stereospecific differences which may exist. This was conducted by measuring the in vitro metabolism of propafenone (racemate and enatiomers) and by developing CYP inhibition screens which could prove to be useful in providing information of potential drug interactions. In addition, stereospecific binding to human albumin was measured to investigate whether any enantiomeric differences in unbound drug exist. For the inhibition studies propafenone (racemate and enatiomers) was incubated in 96 well plates with separate CYP isoforms in the presence of a NADPH regenerating system. CYP activity was monitored using the following fluorogenic substrates: CYP2C19/ CYP1A2 – CEC; CYP2D6 – AMMC; CYP3A4 - BFC. IC50 values were calculated and compared to those of control inhibitors (CYP2C19 – Tranycylpromine; CYP2D6 – Quinidine; CYP3A4 – Ketoconazole ; CYP1A2 - Furafylline). In vitro metabolism was conducted using human liver microsomes incubated with propafenone (racemate and enatiomers) and the degree of metabolism measured using hplc analysis. Protein binding was estimated for propafenone (racemate and enatiomers) by a chromatographic method utilising a chiral HSA column. Inhibition studies showed that the lowest IC50 values were obtained when propafenone …
author: Carroll, Leigh
language: en
keywords: F100 - Chemistry
date published: 2010-08
date modified: 2026-07-24T01:35:35Z
provider: University of Central Lancashire
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Central Lancashire