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PubMedDate not supplied

Relative bioavailability of quinidine gluconate and quinidine sulfate in healthy volunteers.

A comparison of the bioavailability of quinidine sulfate to quinidine gluconate tablets in a single-dose randomized cross-over design with 20 healthy volunteers shows that the sulfate salt is more rapidly absorbed and provides significantly greater peak concentrations 1 hour after administration as compared to the peak levels achieved with the gluconate salt at approximately 5 hours after administration. When adjusted for the actual amount of quinidine contained in each tablet, there was no significant difference in the amount of quinidine bioavailable. Since quinidine gluconate absorption is significantly slower than quinidine sulfate, a combination of the two dosage forms may be utilized in providing the loading dose. Based on the computer modeling and the clinical data accumulated by this laboratory (unpublished) over the past four years, quinidine gluconate, in the dosage form utilized in this study, provides more constant blood levels with smaller differences between the Cpmax and Cpmin than the sulfate when administered every 6 or 8 hours. Further controlled clinical studies are needed to confirm these observations in patients.

Adult↗

PubMedDate not supplied

Bioavailability of a commercial sustained-release quinidine tablet compared to oral quinidine solution.

The bioavailability of quinidine sulfate after oral administration of a commercial sustained-release quinidine tablet was compared with that of oral quinidine sulfate solution in 18 normal subjects. Three hundred milligrams of each product was administered to each subject in standard cross-over fashion on separate occasions, with plasma quinidine levels measured for 46 h after each dose. Although peak plasma quinidine levels were lower, and occurred later, after tablet administration than after solution, analysis of the area under the plasma quinidine level-time curve (AUC) values for each product indicated that the products were equivalent, in terms of the extent of absorption, with the mean AUC (0-46 h) value for the tablet, 8744 . 4 ng x h ml-1, comparable to that of the solution, 9145 . 9 ng x h ml-1.

Administration, Oral↗

PubMed2000

Stereospecificity of antibody: quinine, the optical isomer of quinidine and anti-malarial drug chloroquine do not cross-react with quinidine immunoassays.

Quinine is an optical isomer of quinidine. Both quinine and chloroquine (an aminoquinoline derivative) are used in treating malaria. The authors studied cross-reactivity of quinine and chloroquine with the quinidine immunoassays using the TDx and AxSYM analyzers (Abbott Laboratories, Abbott Park, IL). The authors observed no cross-reactivity of chloroquine with quinidine immunoassays (TDx and AXSYM) even when drug-free serum was supplemented with 1000 microg/mL chloriquine. The authors observed no cross-reactivity of quinine up to a concentration of 250 microg/mL. At higher concentrations, the authors observed a small cross-reactivity. The cross-reactivity of a substance should be studied in the presence of the primary analyte. When serum pools prepared from patients receiving quinidine were supplemented with various concentrations of quinine or chloroquine, the authors observed statistically significant declines in quinidine concentrations with higher concentrations of both quinine and chloroquine. The authors observed significant cross-reactivity of L-amphetamine with the amphetamine immunoassay also marketed by Abbott Laboratories and run on the AxSYM analyzer. The authors conclude that although the antibody used in the quinidine assay is stereospecific, the antibody used in the amphetamine assay by the same manufacturer is not stereospecific.

Antibodies↗

PubMed1983

Changes in steady state digoxin pharmacokinetics during quinidine therapy in cardiac patients: influence of plasma quinidine concentration.

In seven cardiac patients on long-term digoxin therapy, digoxin kinetics were investigated - in the absence and presence of quinidine - after simultaneous administration of an oral digoxin dose and an intravenous 3H-digoxin bolus injection. From 3H-digoxin data quinidine was found to decrease both renal (from 1.19 +/- 0.35 to 0.86 +/- 0.21 ml/min./kg) (P less than 0.02) and extrarenal clearances of digoxin (from 0.85 +/- 0.24 to 0.49 +/- 0.23 ml/min./kg) (P less than 0.02), and to diminish the steady state distribution volume of the drug (from 6.78 +/- 1.23 to 5.63 +/- 1.64 l/kg) (P less than 0.02). Plasma half-life increased from 51.5 +/- 5.4 to 64.4 +/- 14.8 hrs (P less than 0.05), while urinary excretion half-life increased from 54.4 +/- 3.9 to 78.5 +/- 14.1 hrs (P less than 0.01). Pharmacokinetic parameters derived from plasma and urinary digoxin data showed similar changes during quinidine therapy. Reduction in renal 3H-digoxin clearance occurred at subtherapeutic plasma quinidine levels and was independent of plasma quinidine, whereas reductions in extrarenal 3H-digoxin clearance and 3H-digoxin distribution volume were positively correlated to plasma quinidine concentrations (P less than 0.05).

Creatinine↗

PubMed1981

Quinidine-digoxin interaction: effect of quinidine on 86Rb-uptake of human erythrocytes.

Co-administration of quinidine results in a marked increase in serum digoxin concentration (SDC). The implication of this increase in SDC in regard to an increased digoxin effect on the heart is controversial. The 86Rb-erythrocyte-assay represents a perfect model to study whether quinidine interferes with digoxin at the Na-K-ATPase (the so called glycoside receptor) and thus presumably with the inotropic effect of the glycoside. The inhibitory effect of digoxin (0-150 ng/ml) on the 86Rb-uptake was measured in the absence and presence of quinidine in therapeutic or higher concentrations (0-60 microgram/ml). Addition of quinidine produced no effect on digoxin-induced inhibition of Na-K-ATPase activity. Together with our clinical observations these results strongly suggest that the increased SDC during concomitant quinidine therapy actually reflects an increased digoxin effect on the heart.

Digoxin↗

PubMed1991

High-performance liquid chromatographic method for the quantitation of quinidine and selected quinidine metabolites.

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.

Chromatography, High Pressure Liquid↗

PubMed1976

Serum quinidine levels after chronic administration of four different quinidine formulations.

The serum levels produced by four different quinidine formulations have been studied. The relative bioavailability of the formulations was demonstrated as were the mean peak serum levels and their timing in relation to dosage. From the data obtained, the biological half-lives were measured and the apparent volume of distribution and total body clearance were calculated for each formulation. The generic tablets of quinidine monosulphate from five different manufacturers were not significantly different from each other in any respect and produced the expected peak and trough serum level curves. The serum level curves resulting from administration of quinidine polygalacturonate (Cardioquin) were not significantly different from those resulting from the generic tablets, and this formulation may be regarded as therapeutically equivalent to the generic formulations. Both sustained-release formulations of quinidine bisulphate, Durettes and Kiditard (given at the same dosage) were shown to offer a means whereby, with simple twice-daily dosage, quinidine maintenance treatment may be continued with the confidence that the serum levels may be maintained throughout each 24-hour period without peaks into the toxic levels and troughs into the levels of no effect.

Adult↗

PubMed1992

Relationship between serum quinidine concentration and quinidine dosage.

This retrospective study was designed to identify and assess which patient-specific factors affect the relationship between the steady-state trough serum quinidine concentration (SQC) measured by fluorescence polarization immunoassay and quinidine dosage. Data were obtained from 100 hospitalized patients (72 males, 28 females) receiving quinidine for atrial or ventricular arrhythmias, or both, between ages 24 and 85 years (mean age 63 yrs). Age, lean body weight, creatinine clearance (ClCr), and sex were statistically significant factors affecting this relationship; ejection fraction, total body weight, smoking history, alcohol history, recent myocardial infarction, recent surgery, elevated liver function tests, and sampling time were not statistically significant. The ClCr alone provided the most additional information in predicting SQC, and ClCr and weight provided the most additional information in predicting dosage. Currently in clinical practice, quinidine dosage adjustments are not routinely recommended for patients with renal insufficiency. These data suggest that the calculated ClCr is important in predicting both SQC and dosage when a nonspecific quinidine assay is used. This dosing model must be evaluated prospectively.

Adult↗

PubMed1994

Determination of quinidine, dihydroquinidine, (3S)-3-hydroxyquinidine and quinidine N-oxide in plasma and urine by high-performance liquid chromatography.

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.

Chromatography, High Pressure Liquid↗

PubMed1984

Analysis of Cinchona alkaloids by high-performance liquid chromatography. Application to the analysis of quinidine gluconate and quinidine sulfate and their dosage forms.

The application of high-performance liquid chromatography to resolve the individual alkaloids present in marketed Cinchona alkaloids was investigated. Normal-phase and several reversed-phase systems were evaluated. The proposed procedure uses an alkylphenyl column; it adequately resolves quinidine, quinine, dihydroquinidine, dihydroquinine, cinchonine, cinchonidine, dihydrocinchonine and dihydrocinchonidine. Epiquinidine, epiquinine, quininone and quinitoxine are also resolved from quinidine and dihydroquinidine. This high degree of resolution enables the analysis of quinidine and its salts for their usual composition and establishes the absence of any cross-contamination or decomposition. The proposed procedure was applied to currently marketed samples of quinidine salts and their dosage forms. It was also applied to samples that were cross-contaminated or which contained decomposition products.

Capsules↗

PubMedDate not supplied

Synthesis of 10,11-dihydroxydihydroquinidine N-oxide, a new metabolite of quinidine. Preparation and 1H-nmr spectroscopy of the metabolites of quinine and quinidine and conformational analysis via 2D COSY nmr spectroscopy.

The first synthesis of 10,11-dihydroxydihydroquinidine N-oxide [7b], a recently isolated metabolite of quinidine, was accomplished in three steps from 1b. The related congener 7a in the quinine series was also prepared, as well as two other analogues 3a and 4a. In addition, the previously reported human metabolites 2a, 5a, and 6a of quinine [1a] and those 2b, 3b, 4b, 5b, and 6b of quinidine [1b] were synthesized. The chemical shift and coupling constants for all of the metabolites of quinine and quinidine were assigned via 2D COSY 1H-nmr spectroscopy. Moreover, the conformations of these metabolites in solution were found to parallel those of the parent alkaloids, quinine [1a] and quinidine [1b], respectively.

Molecular Conformation↗

PubMedDate not supplied

Polylactic acid microspheres containing quinidine base and quinidine sulphate prepared by the solvent evaporation method. III. Morphology of the microspheres during dissolution studies.

Poly(dl-lactide) (PLA) microspheres containing quinidine or quinidine sulphate were prepared by the emulsification-solvent evaporation technique. The in vitro release profile of quinidine or quinidine sulphate from the microspheres was characterized by three phases: a lag time, a rapid release phase (burst), and a slow release phase. Drug release was studied as a function of the ionic strength of the dissolution medium, to demonstrate the importance of the water imbition into the microspheres which induced the drug release. The lag time increased with increasing ionic strength. The microspheres stayed intact during the dissolution study as shown by scanning electron microscopy (SEM). Disintegration of microspheres which was initially observed was an artifact introduced during the SEM procedure. The high vacuum applied either during the coating of the microspheres with gold-palladium or during the actual observation in the scanning electron microscope caused the microspheres to collapse or rupture.

Chemical Phenomena↗

PubMed1999

In vitro metabolism of quinidine: the (3S)-3-hydroxylation of quinidine is a specific marker reaction for cytochrome P-4503A4 activity in human liver microsomes.

The aim of this study was to evaluate the (3S)-3-hydroxylation and the N-oxidation of quinidine as biomarkers for cytochrome P-450 (CYP)3A4 activity in human liver microsome preparations. An HPLC method was developed to assay the metabolites (3S)-3-hydroxyquinidine (3-OH-Q) and quinidine N-oxide (Q-N-OX) formed during incubation with microsomes from human liver and from Saccharomyces cerevisiae strains expressing 10 human CYPs. 3-OH-Q formation complied with Michaelis-Menten kinetics (mean values of Vmax and Km: 74.4 nmol/mg/h and 74.2 microM, respectively). Q-N-OX formation followed two-site kinetics with mean values of Vmax, Km and Vmax/Km for the low affinity isozyme of 15.9 nmol/mg/h, 76.1 microM and 0.03 ml/mg/h, respectively. 3-OH-Q and Q-N-OX formations were potently inhibited by ketoconazole, itraconazole, and triacetyloleandomycin. Isozyme specific inhibitors of CYP1A2, -2C9, -2C19, -2D6, and -2E1 did not inhibit 3-OH-Q or Q-N-OX formation, with Ki values comparable with previously reported values. Statistically significant correlations were observed between CYP3A4 content and formations of 3-OH-Q and Q-N-OX in 12 human liver microsome preparations. Studies with yeast-expressed isozymes revealed that only CYP3A4 actively catalyzed the (3S)-3-hydroxylation. CYP3A4 was the most active enzyme in Q-N-OX formation, but CYP2C9 and 2E1 also catalyzed minor proportions of the N-oxidation. In conclusion, our studies demonstrate that only CYP3A4 is actively involved in the formation of 3-OH-Q. Hence, the (3S)-3-hydroxylation of quinidine is a specific probe for CYP3A4 activity in human liver microsome preparations, whereas the N-oxidation of quinidine is a somewhat less specific marker reaction for CYP3A4 activity, because the presence of a low affinity enzyme is demonstrated by different approaches.

Algorithms↗

PubMed1978

[Ventricular fibrillation under quinidine medication--quinidine syncope (author's transl)].

Ventricular fibrillation which may occur unexpected under quinidine medication--called quinidine syncope--is one of the most dangerous complications of quinidine application. These life threatening accidents occur in 0,5-4,4% treated cases. The quinidine syncope occurs mostly at the attempt to eliminate atrial fibrillation or flutter. This dangerous side effect is dose independent. The ECG shows an increased QT duration and large U-waves. It seems to be a reentry-tachycardia caused by unequal recovery times in different parts of the ventricular myocardium.

Digitoxin↗

PubMed1990

Quinidine oxidative metabolism. Identification and biosynthesis of quinidine 10,11-dihydrodiol stereoisomers.

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.

Animals↗

PubMed2001

Capillary electrophoretic separation, immunochemical recognition and analysis of the diastereomers quinine and quinidine and two quinidine metabolites in body fluids.

The capillary electrophoretic separation and immunochemical recognition of the two naturally fluorescing, cationic diastereomers quinine (QN) and quinidine (QD), their hydroderivatives and two major QD metabolites (3-hydroxyquinidine and quinidine-N-oxide) was investigated. Plain aqueous phosphate buffers and an alkaline buffer containing dodecyl sulfate micelles are shown to be incapable of resolving the two diastereomers. However, incorporation of an additional chemical equilibrium (with beta-cyclodextrin) in the case of capillary zone electrophoresis (CZE) and the presence of a small amount of an organic solvent as buffer modifier (2-propanol) in dodecyl sulfate based micellar electrokinetic capillary chromatography (MECC), were found to provide separation media which lead to complete resolution of QN, QD and the other compounds of interest. Furthermore, for MECC- and CZE-based immunoassay formats, a commercially available antibody against QD was found to be a perfect discriminator between QD and QN. It was determined to recognize QD and the two QD metabolites (cross reactivity of 20--30%) but not QN. MECC and CZE with laser induced fluorescence (LIF) detection are shown to be suitable to determine QD and metabolites in urine and plasma (quinidine-N-oxide only) collected after single dose intake of 50 mg QD sulfate and of QN in urine, saliva and serum samples that were collected after self-administration of 0.5 l of quinine water (25 mg of QN). With direct injection of a body fluid, MECC with LIF was found to provide 10 ng/ml detection limits for QD and QN. This ppb sensitivity is comparable to that obtained in HPLC assays that are based upon drug extraction. Furthermore, MECC and CZE assays with UV detection are shown to provide the ppm sensitivity required for therapeutic drug monitoring and clinical toxicology of QD and QN.

Body Fluids↗

PubMedDate not supplied

An HPLC method for the quantitation of quinidine and its metabolites in plasma: an application to a quinidine-phenytoin drug interaction study.

A rapid and simple method is described for the separation of quinidine (Q), its metabolites 3-hydroxyquinidine (30HQ) and 2'oxoquinidinone (QD) as well as the quinidine salt contaminant, dihydroquinidine (DHQ) in plasma by high pressure liquid chromatography (HPLC). A silica column was used with methanol: 1 N ammonium nitrate: 2 N ammonium hydroxide (28:1:1 v/v) as the mobile phase to separate the compounds and a fluorescence spectrophotometer for detection. Application of this method is demonstrated by the analysis of human plasma samples collected from a volunteer during a phenytoin-quinidine drug interaction study.

Chromatography, High Pressure Liquid↗

PubMed1977

Bioavailability of quinidine in slow-release form. A comparison between two preparations containing quinidine bisulphate as the active constituent.

Two different slow-release preparations of quinidine bisulphate (A and B) have been tested. The in vitro dissolution rate of preparation B was substantially lower in intestinal than in gastric juice, whereas the release rate of quinidine from preparation A was virtually unaffected by the pH of the dissolution medium. After a single dose of two tablets of each of the preparations to 6 healthy volunteers, corresponding to 386 mg (B) and 320 mg of quinidine base (A), the maximum plasma concentration was attained after about 4.5 h. The peak concentration was 5.2 +/- 0.5 mumol/l for preparation A and 4.1 +/- 0.4 mumol/l for B. A similar difference was found in the area under the plasma concentration curve (AUC), which was 68 +/- 10 mumol-h/l and 54 +/- 5 mumol-h/l, respectively. Taking into consideration that preparation B contained 20.6% more active drug per tablet these values indicate that the extent of bioavailability is about 50% higher for tablet A than for tablet B.

Administration, Oral↗