quinidine-n-oxide and 3-hydroxyquinidine

A specific and sensitive method for the quantitation of quinidine, (3S)-3-hydroxyquinidine, quinidine N-oxide, and dihydroquinidine in plasma and urine has been developed. The method is based on a single-step, liquid-liquid extraction procedure, followed by isocratic reversed-phase high-performance liquid chromatography, with fluorescence detection. After extraction from 250 microliters plasma and 100 microliters urine, the limit of determination is 10 nM and 25 nM, respectively. For the use as standards, commercially available quinidine was purified from dihydroquinidine; quinidine N-oxide was synthesized.

Topics: Chromatography, High Pressure Liquid; Cyclic N-Oxides; Humans; Indicators and Reagents; Magnetic Resonance Spectroscopy; Parasympatholytics; Quinidine; Spectrometry, Fluorescence

A specific and sensitive assay for the separation and quantitation of quinidine, 3-hydroxyquinidine, quinidine-N-oxide, O-desmethylquinidine and dihydroquinidine is presented. The assay is shown to be sensitive to concentrations of 0.1 microgram/ml for all the above compounds when using a serum sample of 0.1 ml. The standard curve demonstrates linearity at concentrations from 0.1 to 5 micrograms/ml. The extraction procedure consists of adjusting the serum to an alkaline pH and extracting once with a mixture of methanol-dichloromethane (15:85). The organic extract is dried and the residue is solubilized in mobile phase. The chromatographic conditions are an isocratic delivery of the mobile phase 0.01 M K2HPO4-acetonitrile (96:4) through a C18 column at ambient temperature. Detection of the compounds of interest is by ultraviolet absorption at a wavelength of 210 nm. For each compound the inter-assay variation is less than 10% and the intra-assay variation is less than 15%. No interfering compounds were detected when a commercially prepared serum spiked with 28 commonly used therapeutic compounds was assayed by this method. The analytical method presented here for the isolation and quantitation of quinidine, several active metabolites, and dihydroquinidine has adequate sensitivity and specificity for monitoring the concentration of quinidine and quinidine metabolites in patient samples.

Topics: Chromatography, High Pressure Liquid; Cyclic N-Oxides; Humans; Quinidine; Quinine; Reproducibility of Results; Spectrophotometry, Ultraviolet

The isocratic reversed phase high performance liquid chromatographic method proposed for quinidine metabolic studies facilitates particularly the separation of 10(R) and (S) isomers of quinidine 10,11-dihydrodiols. The finding of each of these forms following a new synthetic pathway allows us to identify and quantify them in biological fluids. These two isomers have especially been observed in rat bile and hepatocyte secretions. The metabolic inducing effect of phenobarbital on the oxidative metabolism of quinidine is verified in rat isolated hepatocytes. Simultaneous secretion of the two dihydrodiols is also verified in human urine by a gas chromatography/mass spectrometry procedure.

Topics: Animals; Bile; Chromatography, High Pressure Liquid; Cyclic N-Oxides; Gas Chromatography-Mass Spectrometry; Humans; Liver; Male; Molecular Structure; Phenobarbital; Quinidine; Quinine; Rats; Rats, Inbred Strains; Stereoisomerism

The urinary metabolite profile of quinidine and the oral clearance of this drug were studied under steady state conditions in five smoking and nine non-smoking patients. No significant differences were observed in the urinary recovery of unchanged quinidine, 3S-3-hydroxyquinidine, 2'-oxoquinidinone or quinidine-N-oxide between smokers and non-smokers. In addition, the plasma clearance of quinidine was not affected by the smoking status of subjects. These results suggest that cigarette smoke does not induce any of the main pathways for quinidine metabolism in a typical patient population and that the consideration of smoking status is of little utility in aiding in the selection of initial dosage regimens for this drug.

Topics: Aged; Cyclic N-Oxides; Humans; Kinetics; Metabolic Clearance Rate; Middle Aged; Quinidine; Smoking

We investigated the antiarrhythmic activity of two major metabolites of quinidine in human, 3-hydroxyquinidine and quinidine-N-oxide, alone and in combination with the parent drug in an experimental model using reperfusion arrhythmias in an isolated rat heart preparation. No definite pharmacological activity could be shown for quinidine-N-oxide up to concentrations of 16 mg/l. Quinidine and 3-hydroxyquinidine prevented ventricular fibrillation and ventricular tachycardia after coronary reperfusion in a concentration-dependent manner. The relationship between the drug concentration in the perfusate and the fractional suppression of arrhythmia could be described adequately for both compounds by the Hill equation. Whereas no difference was found for the Hill coefficient, the estimates of the concentration associated with 50% arrhythmia suppression was significantly higher for 3-hydroxyquinidine (10.7 +/- 0.3 mg/l vs. 2.2 +/- 0.25 mg/l), indicating that the relative potency of the metabolite was only about 20% compared to the parent compound. To investigate the pharmacodynamic interaction of the two compounds the concentration-response curve was determined for quinidine also in the presence of 3-hydroxyquinidine at a constant concentration of 4 mg/l. A method has been derived that allows quantitative assessment of the pharmacodynamic interaction of two compounds for which the concentration-effect relationship can be described by the Hill equation. The results indicate that the antiarrhythmic effects of 3-hydroxyquinidine and quinidine are additive.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cyclic N-Oxides; Heart Rate; In Vitro Techniques; Kinetics; Male; Perfusion; Quinidine; Rats; Rats, Inbred Strains; Structure-Activity Relationship