ABSTRACT
Antazoline is a first-generation antihistaminic agent with antiarrhythmic quinidine-like properties. In some countries, it is widely used for termination of cardiac arrhythmias, especially atrial fibrillation (AF). However, no human pharmacokinetic studies have been conducted with intravenous antazoline. The aim of our study was to develop and validate a novel liquid chromatography/tandem mass spectrometry (LC-MS/MS) method for the determination of antazoline in human plasma: the ELEPHANT-I [ELEctrophysiological, pharmacokinetic and hemodynamic effects of PHenazolinum (ANTazoline mesylate)] human pharmacokinetic study. Antazoline was extracted from plasma using liquid-liquid extraction. The concentration of the analyte was measured by LC-MS/MS with xylometazoline as an internal standard. The method was validated for linearity, precision, accuracy, stability (freeze/thaw stability, stability in autosampler, short and long term stability), dilution integrity and matrix effect. The analyzed validation criteria were fulfilled. The method was applied to a pharmacokinetic study involving 10 healthy volunteers. Following a single intravenous dose of antazoline mesylate (100 mg), the plasma concentration profile showed a relative fast elimination with a terminal elimination half-life of 2.29 h. A relatively high volume of distribution was observed (Vss=315 L). The values of mean residence time (MRT∞), area under the curve (AUC∞) and clearance were 3.45 h, 0.91 mg h L(-1) and 80.5 L h(-1), respectively. One volunteer showed significant differences in pharmacokinetic parameters. In conclusion, the proposed new LC-MS/MS method was successfully used for the first time for the determination of antazoline in human plasma.
Subject(s)
Antazoline/blood , Antazoline/pharmacokinetics , Chromatography, Liquid/methods , Mesylates/blood , Mesylates/pharmacokinetics , Plasma/chemistry , Tandem Mass Spectrometry/methods , Adult , Antazoline/chemistry , Drug Stability , Female , Half-Life , Hemodynamics/physiology , Humans , Liquid-Liquid Extraction/methods , Male , Mesylates/chemistry , Reproducibility of ResultsABSTRACT
A reversed-phase ion pair chromatography method with liquid-liquid extraction analytical method was developed and validated for the determination of antazoline hydrochloride in plasma and excreta of rat. The aim of our study was to characterize the preclinical pharmacokinetics and excretion profiles of antazoline hydrochloride in rats after intravenous injection at the dose of 10 mg/kg. Plasma and excreta samples were extracted with ethyl acetate, and phenacetin was used as the internal standard. The result showed that the method is suitable for the quantification of antazoline hydrochloride in plasma and excreta samples. Analysis of accuracy (90.89-112.33%), imprecision (<7.1%) and recovery (>82.5%) showed adequate values. After a single intravenous administration at 10 mg/kg to rats, plasma concentration profile showed a relative fast elimination proceeding with a terminal elimination half-life of 3.53 h. Approximately 61.8 and 14.2% of the administered dose were recovered in urine and bile after 72 and 24 h post-dosing respectively; 5.9% of the administered dose was recovered in feces after 72 h post-dosing. The above results show that the major elimination route is urinary excretion.
Subject(s)
Antazoline/analysis , Chromatography, Reverse-Phase/methods , Animals , Antazoline/chemistry , Antazoline/pharmacokinetics , Bile/chemistry , Feces/chemistry , Female , Linear Models , Male , Rats , Rats, Sprague-Dawley , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
Both carcinogenic and non-carcinogenic nitrosamines can be formed under physiological conditions in the human body as a reaction between nitrite and a secondary or tertiary amine. A major part of the population is exposed daily through drinking water to high levels of nitrate, which can be reduced to nitrite. Moreover, nitrate and nitrite are both present in vegetables and nitrite is used in food preservation. Dietary exposure to amines is normally well below 100 mg per day, whereas paracetamol and antazoline, both secondary amines, are used therapeutically at much higher doses. Knowledge about the possible interactions between these widely used drugs and the background exposure to nitrite is presently not available. Therefore, an evaluation of the carcinogenic hazard related to this combination is needed.
