Propafenone (PPF) is a class IC antidysrhythmic drug, which is commonly used for the treatment of atrial fibrillation and other supraventricular arrhythmias. It is also a β-adrenoceptor antagonist that can cause bradycardia and bronchospasm. Hepatotoxicity is one of the adverse reactions reported, with clinical manifestations including acute cholestasis and hepatocyte necrosis. However, the mechanism of PPF-induced hepatotoxicity remains unclear. The present study was conducted to identify reactive metabolite(s) to determine related metabolic pathways and define the possible association of the bioactivation with PPF cytotoxicity. An O-demethylation phase I metabolite (M1), a further position C5 hydroxylation (para-position of the benzene ring) metabolite (M2), glutathione (GSH) conjugates (M3 and M4), and N-acetylcysteine (NAC) conjugates (M5 and M6) were detected in rat liver microsomal incubations containing PPF and GSH or NAC as trapping agents. The corresponding GSH conjugates and NAC conjugates were found in the bile and urine of rats after PPF administration, respectively. The observed GSH and NAC conjugates indicate that a quinone metabolite was generated in vitro and in vivo. Recombinant P450 enzyme incubations showed that CYP2D6 was the principal enzyme catalyzing this metabolic activation. Quinidine, a selective inhibitor of CYP2D6, attenuated the susceptibility of hepatocytes to the cytotoxicity of PPF. The results suggest that PPF was metabolized to a p-quinone intermediate which may be involved in PPF-induced hepatotoxicity.
Propafenone hydrochloride (PPF) is an antiarrhythmic drug used for the treatment of heart diseases with complex pharmacokinetics and a strict requirement on dosage. Current analytical methods for PPF determination require expensive instruments or much time for sample pre-treatment. Thus, it is urgent to establish a simple and time-saving approach for PPF determination. In this work, the dual emissive carbon dots (DECDs) were synthesized through one-step solvothermal treatment with m-aminophenol and citric acid. Two separate fluorescence emission peaks at 340 nm and 420 nm of DECDs are observed under the excitation wavelength of 306 nm. In the presence of PPF, the fluorescence signal at 340 nm decreased, while the signal at 420 nm gradually increased. We interestingly found that the fluorescence signal ratio (F 420 /F 340 ) linearly changed with the concentration of PPF. Therefore, a simple and time-saving ratiometric fluorescent approach for the determination of PPF was developed using DECDs as a probe, showing an excellent linear range from 900 to 100 μM. The detection limit is calculated to be 88 nM. It is a simple and low-cost strategy for PPF detection. The content of PPF was successfully analyzed in commercial tablets and in complex biological samples with satisfactory recoveries (ranging from 97.1 to 103.3%), showing great potential for application in clinical research.
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