Identification and determination of phase I metabolites of propafenone in rat liver perfusate.
Propafenone (PF) is a class 1C antiarrhythmic agent. To study the mechanisms of PF interactions with dietary nutrients in isolated, perfused rat livers, metabolites of PF in liver perfusate were identified and an analytical method was developed for these metabolites plus parent drug. Identification of phase I metabolites was performed using HPLC/MS equipped with a Lichrospher RP-18 column and tandem mass spectrometry (MS/MS) with electrospray and atmospheric pressure chemical ionizations. Three major metabolite peaks, whose protonated molecular ions were m/z 358, 358 and 300, were identified as a propafenone derivative hydroxylated in the omega-phenyl ring (omega-OH-PF), 5-hydroxypropafenone (5-OH-PF), and N-despropylpropafenone (N-des-PF). The levels of omega-OH-PF, 5-OH-PF, N-des-PF and PF were determined simultaneously by HPLC with UV detection at 210 nm and a mobile phase of 0.03% triethylamine and 0.05% phosphoric acid in water-acetonitrile-methanol (45:20:35, v/v/v) after extraction with 5 ml diethyl ether at pH 10.0 and evaporation of solvent under nitrogen. The results revealed that omega-OH-PF, which was not found in humans, was the major metabolite of PF in rat liver perfusate, not 5-OH-PF which is the major metabolite in human plasma.
Tan
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W
College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Canada.
Li
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Q
McKay
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Semple
H A
HA
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000032:analysis* / Q000493:pharmacokinetics*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008099:Liver / Q000378:metabolism*; D008297:Male; D013058:Mass Spectrometry; D011405:Propafenone / Q000032:analysis* / Q000493:pharmacokinetics*; D011786:Quality Control; D051381:Rats; D017207:Rats, Sprague-Dawley; D012015:Reference Standards; D013056:Spectrophotometry, Ultraviolet
D000889:Anti-Arrhythmia Agents; D007202:Indicators and Reagents; D011405:Propafenone