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Purpose: This study assessed the influence of mdr1a P-glycoprotein (P-gp) gene disruption, gender and concentration on initial brain uptake clearance (Clup) of morphine, quinidine and verapamil., Methods: Clup of radiolabeled substrates was determined in P-gp-competent and deficient [mdr1a(-/-)] mice by in situ brain perfusion. Brain:plasma distribution of substrates after i.v. administration was determined in both strains., Results: Genetic disruption of mdr1a P-gp resulted in 1.3-, 6.6- and 14-fold increases in Clup for morphine, verapamil and quinidine, respectively. With the exception of small differences for verapamil, gender did not affect Clup. Saturable transport of verapamil and quinidine was observed only in P-gp-competent mice, with apparent IC50 values for efflux of 8.6 +/- 2.3 microM and 36 +/- 2 microM, respectively. Verapamil Clup was approximately 50% higher in mdr1a(+/-) vs. mdr1a(+/+) mice; no such difference was observed for quinidine. In P-gp-competent mice, uptake of verapamil and quinidine was unaffected by organic vehicles. Plasma decreased VER Clup to a greater extent in the presence of P-gp. The influence of P-gp in situ was lower than, but correlated with, the effect in vivo., Conclusions: P-gp decreases Clup of morphine, verapamil and quinidine in situ with little or no influence of gender, but this effect cannot fully account for the effects of P-gp in vivo. P-gp is the only saturable transport mechanism for verapamil and quinidine at the murine blood-brain barrier. The influence of protein binding on Clup may be enhanced by P-gp-mediated efflux.

Objective: Ventricular pacing or arrhythmias can induce cardiac memory (CM). We hypothesized that clinically administered antiarrhythmic drugs alter the expression of CM, and that the repolarization changes characteristic of CM can modulate the effects of antiarrhythmic drugs., Methods: We studied conscious, chronically-instrumented dogs paced for two 1-h periods to study the effects of drugs on the evolution of memory (protocol 1) or for 21 days (protocol 2) to observe the effects of steady-state memory on drug actions. Dogs were treated in both settings with quinidine, lidocaine or E4031, in random order, and within therapeutic serum concentration ranges., Results: Pacing, alone, for 2 h significantly prolonged ERP only near the left ventricular pacing site, whereas pacing alone for 21 days prolonged ERP at all sites (P<0.05). Quinidine and E4031, but not lidocaine, prolonged repolarization and ERP and suppressed evolution of CM in protocol 1. However, quinidine's effect in prolonging repolarization was diminished in both protocols, while its effect in prolonging ERP was diminished in the 21-day protocol only. In contrast, the effects of E4031 were additive to those of CM, prolonging repolarization and ERP in both protocols, while lidocaine showed no changes in effect at all., Conclusions: Pacing to induce CM significantly affects ventricular repolarization and refractoriness, and there are interactions between CM, quinidine and E4031. Depending on the specific drug, these interactions have the potential to be anti- or proarrhythmic, and may impact importantly on the clinical efficacy of drugs as well as on electrophysiologic testing of drug actions.

The determination of quinine, (3S)-3-hydroxyquinine, 2'-quininone and (10R)- and (10S)-10,11-dihydroxydihydroquinine in plasma and urine samples is described. This is the first time the R and S configurations have been correctly assigned to the two metabolites of 10,11-dihydroxyquinine. One hundred microliter-plasma samples were protein precipitated with 200 microl cold methanol. Urine samples were 10-100 x diluted and then directly injected into the HPLC. A reversed-phase liquid chromatography system with fluorescence detection and a Zorbax Eclipse XDB phenyl column and gradient elution was used. The within and between assay coefficients of variation of the method for quinine and its metabolites in plasma and urine was less than 13%. The lower limit of quantitation was in the range of 0.024-0.081 microM.

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.

The frequent recurrence of paroxysmal atrial fibrillation (PAF) despite the use of standard antiarrhythmic agents prompted the use of new therapeutic approaches. There are few data on systematic assessment of PAF control with stepwise dose escalation and the use of a drug combination. Low-dose quinidine may promote the efficacy of propafenone by inhibiting its degradation through the cytochrome P450 pathway (CYP2D6). We prescribed propafenone 300 to 450 mg/day to 60 patients with PAF for 8 weeks, and 62% were symptomatically controlled. The 19 refractory patients were randomized in a double-blinded fashion to receive either a higher dose of propafenone (450 to 675 mg/day) or the standard dose of propafenone with low-dose quinidine 150 mg/day, each for an 8-week study period, and subsequently crossed over to the alternative treatment. The resulting serum propafenone concentrations were 259 +/- 208 and 336 +/- 237 mg/day (p >0.5), respectively. Both treatment arms prolonged the time to the first symptomatic atrial fibrillation (AF) recurrence and the interval between attacks, and AF was controlled in 37% of patients. However, the higher dose of propafenone was associated with gastrointestinal side effects not present with the low-dose quinidine combination. Of the 10 refractory patients, 7 were further controlled with a standard dose of propafenone plus quinidine (600 mg/day). Overall, control of PAF was achieved in 85% of patients at the end of 8 months; adverse effects necessitating withdrawal were observed in 6%, and uncontrolled AF in 5% of patients. There was no difference in the mean AF rate during recurrences in all phases, and ventricular proarrhythmia was not seen. This study documents the role of stepwise antiarrhythmic treatment of PAF. The use of a standard dose of propafenone, followed by low-dose quinidine combination to reduce propafenone degradation, and the combined standard dose of propafenone and quinidine may be used to maximize efficacy and tolerability.

Background: In vitro studies have shown that the formation of 3-hydroxyquinidine from quinidine is catalyzed almost exclusively by CYP3A4. In vivo this result has been supported in various interaction studies, and the use of this reaction as an in vivo biomarker reaction of CYP3A4 activity has been suggested. We studied the possible correlation of the formation clearance of 3-hydroxyquinidine with probe-based assays for CYP1A2, CYP2C9, CYP2C19, and CYP2D6. Descriptive analyses of the outcome of various biomarker reactions were performed., Methods: Forty-two healthy, young male volunteers participated in an open study consisting of two identical test periods separated by a 12- to 14-week washout period. In each period biomarker reactions of CYP1A2 (caffeine), CYP2C9 (tolbutamide), CYP2C19 (mephenytoin), CYP2D6 (sparteine), CYP3A4 (urinary excretion of 6beta-hydroxycortisol), as well as the pharmacokinetics of quinidine after a 200-mg single oral dose of quinidine sulfate were studied., Results: The median formation clearance of 3-hydroxyquinidine were 2.40 and 2.33 L/h in the two test periods. As measured by the formation clearance of 3-hydroxyquinidine, the intraindividual coefficient of variation for CYP3A4 activity was 18%, whereas the interindividual activity varied fourfold. The formation clearance of 3-hydroxyquinidine did not correlate with the outcome of indexes for activities of CYP1A2, CYP2C9, CYP2C19, or CYP2D6 or the urinary excretion of 6beta-hydroxycortisol. The formation clearance of 3-hydroxyquinidine correlated well to point values of 3-hydroxyquinidine to quinidine ratios in plasma and urine., Conclusion: The formation clearance of 3-hydroxyquinidine after a single oral dose of 200 mg quinidine sulfate may represent a useful index of CYP3A4 activity in vivo.

Background: Prolongation of the electrocardiographic QT interval by drugs is associated with the occurrence of a potentially lethal form of polymorphic ventricular tachycardia termed torsades de pointes. Women are at greater risk than men for development of this adverse event when taking drugs that prolong the QT interval. To determine whether this may be the result of gender-specific differences in the effect of quinidine on cardiac repolarization, we compared the degree of quinidine-induced QT interval lengthening in healthy young men and women., Methods: Twelve women and 12 men received a single intravenous dose of quinidine (4 mg/kg) or placebo in a single-blind, randomized crossover trial. Total plasma and protein-free concentrations of quinidine and 3-hydroxyquinidine were measured in serum. QT intervals were determined and corrected for differences in heart rate with use of the method of Bazett (QTc = QT/RR1/2)., Results: As expected, the mean QTc interval at baseline was longer for women than for men (mean +/- SD; 407 +/- 7 versus 395 +/- 9 ms, P < .05). The slope of the relationship between change in the QTc interval (delta QTc) from baseline to the serum concentration of quinidine was 44% greater for women than for men (mean +/- SE; 42.2 +/- 3.4 versus 29.3 +/- 2.6 ms/microg per mL, P < .001). These results were not influenced by analysis of 3-hydroxyquinidine, free concentrations of quinidine and 3-hydroxyquinidine, or the JT interval., Conclusions: Quinidine causes greater QT prolongation in women than in men at equivalent serum concentrations. This difference may contribute to the greater incidence of drug-induced torsades de pointes observed in women taking quinidine and has implications for other cardiac and noncardiac drugs that prolong the QTc interval. Adjustment of dosages based on body size alone are unlikely to substantially reduce the increased risk of torsades de pointes in women.

Aims: To study whether the CYP2D6 capacity in ultrarapid metabolizers of debrisoquine due to duplication/multiduplication of a functional CYP2D6 gene, can be 'normalised' by low doses of the CYP2D6 inhibitor quinidine and whether this is dose-dependent., Methods: Five ultrarapid metabolizers of debrisoquine with 3, 4 or 13 functional CYP2D6 genes were given single oral doses of 5, 10, 20, 40, 80 and 160 mg quinidine. Four hours after quinidine intake, 10 mg debrisoquine was given. Urine was collected for 6 h after debrisoquine administration. Debrisoquine and its 4-hydroxymetabolite were analysed by h.p.l.c. and the debrisoquine metabolic ratio (MR) was calculated., Results: Without quinidine the MR in the ultrarapid metabolizers ranged between 0.01 and 0.07. A dose-effect relationship could be established for quinidine with regard to the inhibitory effect on CYP2D6 activity. To reach an MR of 1-2, subjects with 3 or 4 functional genes required a quinidine dose of about 40 mg, while the sister and brother with 13 functional genes required about 80 mg quinidine. After 160 mg quinidine, the MRs, in the subjects with 3, 3, 4, 13 and 13 functional genes, were 12.6, 10.1, 9.2, 2.4 and 2.2, respectively., Conclusions: A dose-effect relationship could be established for quinidine inhibition of CYP2D6 in ultrarapid metabolizers. The clinical use of low doses of quinidine as an inhibitor of CYP2D6 might be considered in ultrarapid metabolizers taking CYP2D6 metabolized drugs rather than giving increased doses of the drug. Normalizing the metabolic capacity of CYP2D6, by giving a low dose of quinidine, may solve the problem of 'treatment resistance' caused by ultrarapid metabolism.

Recently, several reports of clinical cases of QT prolongation and torsades de pointes, associated with the use of tacrolimus (FK506), have come to light. We have previously demonstrated FK506-induced QT prolongation in guinea pigs [Minematsu T., et al., Life Sci., 65, PL197-PL202 (1999)]. We now examined the relationship between QTc prolongation and the pharmacokinetics of FK506 in guinea pigs, in order to evaluate the arrhythmogenicity of FK506 when compared with that of quinidine sulfate (QND). Thus, dose-response relationships for FK506 (0.01 or 0.1 mg/h/kg) or QND (30 mg/h/kg) were investigated during and after intravenous infusion and also following intravenous bolus administration of FK506 (0.2 mg/kg). The dose-response relationship between plasma drug concentration and QTc prolongation for FK506 and QND were subsequently analyzed using an effect compartment model. The pharmacodynamic parameters thus obtained were as follows: kE0 2.72 x 10(-4) (min-1), Emax 27.1 (ms), EC50 0.376 (ng/ml) for FK506; and kE0 0.148 (min-1), K 8.41 (ms.ml/microgram) for QND. The anti-clockwise hysteresis observed for FK506-induced QT prolongation was successfully analyzed by the present pharmacokinetic/pharmacodynamic model, which may provide a rational basis for developing a clinical dosing regimen to avoid possible QT prolongation induced by FK506.

Objective: To investigate the roles of CYP3A4 and CYP1A2 in the 3-hydroxylation of quinine in vivo., Methods: In a randomized, three-way crossover study, nine healthy Swedish volunteers received single oral doses of quinine hydrochloride (500 mg), quinine hydrochloride (500 mg) plus ketoconazole (100 mg twice daily for 3 days), and quinine hydrochloride (500 mg) plus fluvoxamine (25 mg twice daily for 2 days) on three different occasions. Blood and urine samples were collected before quinine intake and up to 96 hours thereafter. Plasma and urine samples were analyzed for both quinine and its main metabolite 3-hydroxyquinine with HPLC methods., Results: Coadministration with ketoconazole (which inhibits CYP3A4) decreased the mean apparent oral clearance of quinine significantly (P < .001) by 31% (from 8.7 to 6.0 L/h), whereas coadministration with fluvoxamine (which inhibits CYP1A2 and to some extent CYP2C19) had no significant effect (P > .05) on the mean apparent oral clearance of quinine. Coadministration with ketoconazole also decreased the mean area under the plasma concentration versus time curve (AUC) of 3-hydroxyquinine (from 28.4 to 19.7 micromol x h x L(-1); P < .001), whereas coadministration with fluvoxamine increased 3-hydroxyquinine AUC significantly (from 28.4 to 30.2 micromol x h x L(-1); P < .05)., Conclusion: Cytochrome P450 3A4 is important for the 3-hydroxylation of quinine in vivo. On the other hand, CYP1A2 had no significant effect on this metabolic pathway.

Objective: As quinine is mainly metabolised by human liver CYP3A4 and grapefruit juice inhibits CYP3A4, the effect of grapefruit juice on the pharmacokinetics of quinine following a single oral dose of 600 mg quinine sulphate was investigated., Methods: The study was carried out in ten healthy volunteers using a randomised cross-over design. Subjects were studied on three occasions, with a washout period of 2 weeks. During each period, subjects received a pretreatment of 200 ml orange juice (control), full-strength grapefruit juice or half-strength grapefruit juice twice daily for 5 days. On day 6, the subjects were given a single oral dose of 600 mg quinine sulphate with 200 ml of one of the juices. Plasma and urine samples for measurement of quinine and its major metabolite, 3-hydroxyquinine, were collected over a 48-h period and analysed by means of a high-performance liquid chromatography method., Results: The intake of grapefruit juice did not significantly alter the oral pharmacokinetics of quinine. There were no significant differences among the three treatment periods with regard to pharmacokinetic parameters of quinine, including the peak plasma drug concentration (Cmax), the time to reach Cmax (tmax), the terminal elimination half-life (t1/2), the area under the concentration-time curve and the apparent oral clearance. The pharmacokinetics of the 3-hydroxyquinine metabolite were slightly changed when volunteers received grapefruit juice. The mean Cmax of the metabolite (0.25+/-0.09 mg l(-1), mean +/- SD) while subjects received full-strength grapefruit juice was significantly less than during the control period (0.31+/-0.06 mg l(-1), P < 0.05) and during the intake of half-strength grapefruit juice (0.31+/-0.07 mg l(-1), P < 0.05)., Conclusion: These results suggest that there is no significant interaction between the parent compound quinine and grapefruit juice, so it is not necessary to advise patients against ingesting grapefruit juice at the same time that they take quinine. Since quinine is a low clearance drug with a relatively high oral bioavailability, and is primarily metabolised by human liver CYP3A4, the lack of effect of grapefruit juice on quinine pharmacokinetics supports the view that the site of CYP inhibition by grapefruit juice is mainly in the gut.

The relative binding of acetaminophen, lidocaine, phenobarbital, procainamide, quinidine, and theophylline to sera of seven mammalian species was studied. Pooled commercial sera from cow, goat, horse, human, pig, rabbit, and sheep were supplemented with 5 and 10 mM concentrations of each drug. For each serum, each drug, and each drug concentration, equilibrium dialysis was performed in duplicate against phosphate buffer (pH 7.4, 0.1 M, 4 degrees C). Percent drug bound to serum was calculated. Phenobarbital demonstrated more than 20% binding to goat, horse, human, and sheep serum at both 5 and 10 mM concentrations; more than 20% binding to bovine serum at a concentration of 10 mM; and more than 20% binding to pig and rabbit serum at 5 mM. Quinidine (studied only at 5mM concentration) bound more than 20% to cow, goat, horse, human, pig, and rabbit serum. In contrast, procainamide at both the 5 and 10 mM concentrations showed no binding to cow, horse, pig, rabbit, or sheep serum. Acetaminophen (studied only at 5 mM concentration), lidocaine, and theophylline demonstrated less than 20% binding to each serum. Acetaminophen at 5 mM did not bind to human serum, and lidocaine at 10 mM did not bind to horse or pig serum. Although some interspecies variation in drug binding to the seven sera was noted, the overall magnitude of binding of each drug to each serum was, for the most part, similar. Phenobarbital and quinidine showed stronger (> 20%) binding; procainamide showed negligible binding; and acetaminophen, lidocaine, and theophylline demonstrated intermediate (< 20%) binding.

Lidocaine, quinidine, and theophylline binding to normal pooled mature human milk was determined using equilibrium dialysis at 4 degrees C. Binding to milk was compared with binding to pooled human serum. The observed binding was related to the relative lipid solubility of each drug in milk. The potential for the excretion of each drug into milk was also evaluated.

We conducted a prospective, nonrandomized study in healthy volunteers to determine if racial differences exist in orosomucoid (ORM) and its variants, and to examine quinidine and lidocaine binding to the protein. Total ORM serum concentrations were measured by Laurell-Rocket immunoelectrophoresis. Allele types were determined by isoelectric focusing and immunoblotting. Total and unbound quinidine and lidocaine concentrations were measured with standard fluorescence polarization immunoassays after ultrafiltration. The frequency of the common ORM alleles was similar between 38 Caucasians and 67 African-Americans. Mean total ORM concentration was significantly lower in Caucasians (57.3 +/- 25.4 vs 73.2 +/- 33.9 mg/dl, p=0.01). However, more Caucasians took oral contraceptives, which may have decreased ORM concentrations. Quinidine unbound fraction (UF) was related to ORM phenotype. The highest UF was found with ORM 1-S (p=0.009). There were no significant relationships between ORM phenotype and lidocaine UF. Overall, African-Americans had higher ORM concentrations than Caucasians. Quinidine binding showed significant relationships to specific ORM variants.

The determination of 3-hydroxyquinine in urine and plasma samples is described. Extraction was performed using a mixture of toluene-butanol (75:25, v/v), followed by back-extraction into the mobile phase, which consisted of 0.1 M phosphate buffer, acetonitrile, tetrahydrofuran and triethylamine. A reversed-phase liquid chromatography system with fluorescence detection and a CT-sil C18 column were used. The within-assay coefficient of variation of the method was 2% at the higher concentration values in plasma, 2.95 microM, 4% at 227 nM and 9% at the lower limit of quantitation, 4.5 nM. In urine, the coefficient of variation was 11% at the lower concentration, 227 nM and was 3% at 56.8 microM. The between-assay coefficient of variation was 4% at the low concentration (5.1 nM) in plasma, 2% at 276.8 nM and 3% at 1.97 microM. In urine, the between assay coefficient of variation was 4% at 204.6 nM, 3% at 5.12 microM and 2% at 56.8 microM.

Background: Quinidine is eliminated mainly by CYP3A4-mediated metabolism. Itraconazole interacts with some but not all of the substrates of CYP3A4; it is therefore important to study the possible interaction of itraconazole with quinidine., Methods: A double-blind, randomized, two-phase crossover study design was used with nine healthy volunteers. Itraconazole (200 mg) or placebo was ingested once a day for 4 days. A single 100 mg oral dose of quinidine sulfate was ingested on day 4. Plasma concentrations of quinidine, itraconazole, and hydroxyitraconazole, as well as cumulative excretion of quinidine into urine, were determined up to 24 hours. The ECG, heart rate, and blood pressure were also recorded up to 24 hours., Results: On average the peak plasma concentration of quinidine increased to 1.6-fold (p < 0.05), and the area under the concentration-time curve of quinidine increased to 2.4-fold (p < 0.01) by itraconazole. The elimination half-life of quinidine was prolonged 1.6-fold (p < 0.001), and the area under the 3-hydroxyquinidine/quinidine ratio-time curve decreased to one-fifth (p < 0.001) by itraconazole. The renal clearance of quinidine decreased 50% (p < 0.001) by itraconazole, whereas the creatinine clearance was unaffected. The QTc interval correlated with the concentrations of quinidine during both itraconazole and placebo phases (r2 = 0.71 and r2 = 0.79, respectively; p < 0.01), although only minor changes between the phases were observed in other pharmacodynamic variables., Conclusions: Itraconazole increases plasma concentrations of oral quinidine, probably by inhibiting the CYP3A4 isozyme during the first-pass and elimination phases of quinidine. The decreased renal clearance of quinidine might be the result of the inhibition of P-glycoprotein-mediated tubular secretion of quinidine by itraconazole. The concentrations of quinidine should be closely monitored if itraconazole or some other potent CYP3A inhibitors are used with quinidine.

Study Objectives: To determine if alpha1-acid glycoprotein (AAG) concentrations are altered in patients with atrial fibrillation and flutter (AFF), and to establish if fluctuations in AAG change the free fraction of quinidine., Design: Prospective, controlled, nonrandomized., Setting: Tertiary care medical center and outpatient clinics., Patients: Thirty patients with AFF and 16 matched controls., Interventions: Serial blood samples were collected from patients with AFF at baseline and for 28 days after cardioversion. The control group received no treatment and a single blood sample was obtained., Measurements and Main Results: Concentrations of AAG were measured by Laurell-Rocket immunoelectrophoresis. Quinidine concentrations were determined by fluorescence polarization immunoassay using the Abbott TDx system. Baseline AAG concentrations in patients with AFF (122 +/- 55 mg/dl) were significantly increased compared with the control group (62 +/- 28 mg/dl, p<0.0005). Concentrations of AAG remained elevated after conversion to sinus rhythm and did not significantly change over the study period, regardless of method of cardioversion (p>0.2). In patients with AFF, the free fraction of quinidine at the highest AAG concentration was 8.5 +/- 2.3%. This was significantly reduced compared with the value in the control group (12.5 +/- 3.0%, p<0.05) as well as that in patients with AFF at the lowest AAG concentration (11.0 +/- 2.5%, p<0.05). Overall at the highest AAG concentration, patients with AFF had a relative reduction in the quinidine free fraction by 32% compared with controls. Regression analysis showed an indirect relationship between serum AAG concentration and the unbound fraction of quinidine (r=0.56), Conclusions: Concentrations of AAG are increased in patients with AFF and remain elevated for at least 28 days after cardioversion. Elevated AAG concentrations significantly reduce the free fraction of quinidine.

A markedly prolonged quinidine elimination half-life due to hepatic failure and resultant quinidine toxicity occurred in a 57-year-old man with a history of atrial fibrillation. A prolonged QT interval, development of torsades de pointes, and a serum quinidine concentration of 3.1 micrograms/ml contributed to a decision favoring permanent pacemaker implantation. The apparent quinidine half-life ranged from 66-99 hours and was associated with QT prolongation and persistent U waves. On discontinuing quinidine, all signs associated with toxicity resolved as serum quinidine concentrations decreased, which resulted in reversal of the decision to implant a permanent pacemaker. This case reports an extremely long quinidine elimination half-life and reillustrates the importance of drug pharmacokinetics in patient care.

Background: Some cytochrome P450 (CYP) enzymes, including CYP3A, are expressed not only in the liver but also in the intestine; the latter may therefore be an important site of drug disposition. Animal data suggests that dietary salt modulates expression of renal CYPs. We therefore hypothesized that intestinal CYP3A may be similarly modulated by dietary salt., Methods: The effect of changes in dietary salt on the disposition of two CYP3A substrates, quinidine (administered orally and intravenously) and 14C-erythromycin (administered intravenously) were determined after normal volunteers were given high-salt (400 mEq/day) and low-salt (10 mEq/day) diets for 7 to 10 days each., Results: Plasma concentrations after oral quinidine were significantly lower during the high-salt phase, with the difference between the two treatments attributable to changes within the first 1 to 4 hours after administration. For example, the area under the plasma concentration-time curve for the first hour after drug administration was 0.56 +/- 0.38 microgram.hr/ml for the high-salt diet compared with 1.57 +/- 0.60 micrograms.hr/ml for the low-salt diet (p < 0.05). Similarly, the peak plasma concentration (Cmax) achieved was lower and the time to reach Cmax was later for the high-salt diet (p < 0.05). In contrast, the terminal phase elimination half-lives were similar for the two diets, and no differences in disposition were found with the intravenous drug. The erythromycin breath test was unaffected by the dietary treatments., Conclusions: These results indicate an effect of dietary salt on the presystemic disposition of orally administered quinidine. Although the mechanism(s) of CYP3A activity modulation is unknown, this finding may be important in determining drug availability in conditions associated with abnormal salt homeostasis.

The effects of nine reversers of P-glycoprotein on the uptake of daunomycin into MDR1-transfected P388 cells were quantitatively determined in undiluted human or mouse plasma and compared with their effects when measurements are made in a conventional cell culture medium (RPMI 1640) containing only 10% serum. Plasma diminished or greatly diminished the effectiveness of the reversers, reductions of up to 20-fold being found for reversers (cyclosporin A, prochlorperazine and amiodarone) that have been used in clinical trials, although quinidine was almost as effective in plasma as in cell culture medium containing 10% fetal calf serum. Human or bovine serum albumin could mimic the effect of whole plasma. When measurements of the effectiveness of the reverser cyclosporin A were made in an ex vivo assay, using these P388 cells, complete accord was found between such ex vivo determinations and cyclosporin A's effectiveness in vivo, as monitored by its ability to increase the accumulation of vinblastine in mouse kidney tissue. The ex vivo assay was shown to be suitable to monitor the effectivity of reversers present in plasma taken from patients receiving quinidine and cyclosporine A in routine clinical treatment.

The aim of this study was to assess the pharmacokinetics and subsequent pharmacodynamic interaction of MPC-1304, a dihydropyridine Ca2+ antagonist, with other drugs in animal experiments. We measured the systolic blood pressure and heart rate of conscious spontaneously hypertensive rats implanted with battery-operated biotelemetry devices after combined administration of various drugs. Cimetidine (10 mg/kg) did not affect the reduction in systolic blood pressure and the increase in heart rate induced by MPC-1304, whereas it significantly increased the plasma concentration of a metabolite of MPC-1304 (M-1) compared to that detected when MPC-1304 was administered alone. When MPC-1304 was consecutively administered in combination with rifampicin (400 mg/kg) for 9 days, the plasma concentrations of MPC-1304 and of M-1 significantly decreased compared to those found when MPC-1304 alone was given. In spite of these reductions in plasma concentrations, rifampicin did not attenuate the hypotensive action induced by MPC-1304. When prazosin, reserpine, or methyldopa was administered in combination with MPC-1304, the hypotensive action was enhanced as compared to that by MPC-1304 alone or to that by the co-administered drug used alone (prazosin, reserpine, or methyldopa). Quinidine (10 mg/kg) affected neither the hypotensive action induced by MPC-1304 nor the plasma concentrations of MPC-1304 and M-1. These results indicate that cimetidine and rifampicin interact with MPC-1304 pharmacokinetically, without apparently changing the hypotensive action of MPC-1304, whereas quinidine does not affect the metabolism of MPC-1304, and that other hypotensive drugs, such as prazosin, reserpine, and methyldopa, potentiate the hypotensive action of MPC-1304.

Background: Chronic atrial fibrillation (CAF) is a serious condition with significant morbidity and mortality. The mainstay of drug therapy for the conversion of atrial fibrillation to sinus rhythm continues to be quinidine. The value and safety of intravenously (i.v.) administered amiodarone therapy vs quinidine sulfate therapy was compared in a cohort of patients with CAF of more than 3 weeks' duration., Objectives: To evaluate the efficacy of i.v. administered amiodarone and oral quinidine sulfate containing 300 mg of quinidine in the conversion of CAF and to assess the effect of oral amiodarone in the conversion of CAF in the patients in whom CAF did not convert with IV amiodarone., Methods: Thirty-two patients with CAF of more than 3 weeks' duration were randomized to either i.v. amiodarone treatment or oral digoxin/quinidine treatment in a randomized unblinded single crossover study. The converters continued either oral amiodarone therapy or quinidine extended-action tablet (Quinidex) therapy., Results: Seventeen patients were randomized to the quinidine group and 15 patients to the amiodarone group. Nonconverters from the quinidine group crossed over to the amiodarone group. Amiodarone and quinidine were equally effective at 24 hours in converting CAF (eight [47%] of 17 patients in the quinidine group vs 12 [44%] of 27 patients in the amiodarone group; P, not significant). At 2 and 9 months of oral therapy, amiodarone was superior to quinidine in maintaining sinus rhythm. Only two of eight patients in the quinidine group tolerated the medication. All patients in the amiodarone group tolerated the medication. One additional patient converted to sinus rhythm at 2 months (13 [48%] of 27), and five more patients converted at 9 months (18 [67%] of 27). Amiodarone therapy and digoxin/quinidine therapy were equally effective at 48 hours in controlling ventricular response at rest., Conclusions: During the first 48 hours of treatment, i.v. amiodarone and oral quinidine were equally effective in converting CAF to sinus rhythm. At 2 and 9 months of therapy, treatment with oral amiodarone was superior to that of quinidine in restoring sinus rhythm. Long-term treatment with oral amiodarone is better tolerated than with quinidine.

A novel method for simultaneous determination of diltiazem and quinidine in human plasma is described. Plasma is alkalinized and extracted with methyl tert.-butyl ether. The ether phase is separated and evaporated. The residue is reconstituted in 0.2 ml of mobile phase containing 56 mM octanesulfonic acid then washed twice with n-hexane. Aliquots are chromatographed on a silanol-deactivated reversed-phase column using a mobile phase containing aqueous H2SO4 (0.01 M, pH 2)-methanol-acetonitrile (45:45:10) and 10 mM octanesulfonic acid. Peaks are monitored with a UV detector set at 237 nm and a fluorescence detector using an excitation set at 247 nm and a 270 nm UV cut-off filter at the emission. Calibration and standard curves were linear from 1 to 130 ng on-column for diltiazem and from 2 to 600 ng on-column for quinidine. Limits of quantitation were 2 and 4 ng/ml for diltiazem and quinidine, respectively. Recoveries from spiked plasma were 94.0 to 102.5% (R.S.D. 6.0-11.4%) for diltiazem and 98.5% to 104.1 (R.S.D. 7.7-8.7%) for quinidine over the ranges studied. In vitro stability was studied in spiked plasma samples stored at -80 degrees C for sixteen months. Both diltiazem and quinidine remained within 10% from nominal values. For ex vivo stability at -80 degrees C, a plasma sample obtained from a volunteer 2 h after oral administration of diltiazem (60 mg) was analysed for two days after sampling and eighteen months later. The mean deviation from initial measured was 4.7%.

Several clinical investigations have been published regarding the interaction of nifedipine and quinidine. The results of these studies are contradictory. In vitro studies indicate that the 3-hydroxylation and N-oxigenation of quinidine appear to involve the P4503A4 family, a form of cytochrome that predominantly catalyzes the aromatization of nifedipine, too. The aim of our study was to investigate the effect of oral intake of 200 mg quinidine on the kinetics of 20 mg nifedipine as a retarded formulation and vice versa. Twelve healthy male volunteers between 18 and 40 years were treated. Each subject was studied on three occasions each separated by a one week washout period. Drug administration consisted of one oral dose of nifedipine (Adalat retard 20 mg), one oral dose of quinidine (Chinidin sulfuricum "Buchler" 200 mg) or a combination of both (20 mg nifedipine and 200 mg quinidine) in a randomised 3 way crossover. Administration of the test drugs in combination slightly increased the bioavailability of both--nifedipine [N] to 18% and quinidine [Q] to 16%--and decreased the clearance of both drugs. The results were not statistically significant. Based on our data, the combination of nifedipine and quinidine seems to lack a clinically relevant interaction.

The aim of this study was to determine if quinidine administration increases steady state serum digoxin concentration in horses. Digoxin (0.01 mg/kg q. 12 h per os) was administered to 6 horses for 7 days. Steady state was confirmed by identifying statistically indistinguishable peak and trough serum digoxin concentrations on Days 4, 5, and 6. On Day 6, serum digoxin concentration was measured at baseline and 0.25, 0.5, 1, 2, 4, 6, 8 and 12 h after digoxin administration. On Day 7, quinidine (20 g at baseline and 10 g at 2, 4 and 6 h) was administered per os and serum digoxin concentration was measured at the same time intervals. Creatinine and renal digoxin clearances were measured on Days 6 and 7. Results indicated that there was approximately a doubling of serum digoxin concentration (from mean +/- s.d. 2.57 +/- 0.96 ng/ml at baseline to 4.28 +/- 1.31 at 15 min and 5.98 +/- 1.21 ng/ml at 30 min) after starting the administration of quinidine. This elevation persisted for the 12 h after starting quinidine administration. Renal digoxin and endogenous creatinine clearances decreased but the decrease in digoxin clearance was greater. Serum quinidine concentration achieved the therapeutic range (2-6 micrograms/ml) in 5 of the 6 horses. In summary, similar to findings in other species, quinidine administration increases steady state serum digoxin concentration in horses and this occurs, at least in part, due to a decrease in renal digoxin clearance. Some of the decrease in renal clearance is due to decreased glomerular filtration which is dissimilar to findings in other species.

Using fused-silica optical fibres for fluorescence light collection and bandpass filters for selection of emission wavelengths, a capillary electrophoresis detection cell of a conventional, tunable UV-Vis absorbance detector was adapted for simultaneous fluorescence (at selected emission wavelength) and absorbance (at selected excitation wavelength) detection. Detector performance is demonstrated with the monitoring of underivatized fluorescent compounds in body fluids by micellar electrokinetic capillary chromatography with direct sample injection. Compared with UV absorption detection, fluorescence detection is shown to provide increased selectivity and for selected compounds also up to tenfold higher sensitivity. Examples studied include screening for urinary indole derivatives (tryptophan, 5-hydroxytryptophan, tyrosine, 3-indoxyl sulfate and 5-hydroxyindole-3-acetic acid) and catecholamine metabolites (homovanillic acid and vanillylmandelic acid) and the monitoring of naproxen in serum, quinidine in serum and urine and of salicylate and its metabolites in serum and urine.

A study of the influence of the aluminum ion on the blood and hepatic kinetics of two alkaloid stereoisomers--quinine and quinidine--after their p.o. and s.c. administration (80 mg/kg) to rats was carried out. It appeared that the mode of application of the stereoisomers had different effects on their resorbtion in control animals. In the case of s.c. application, blood concentrations of quinine in some time intervals reached significantly higher levels than those found for quinidine. Hepatic elimination of quinine appeared to be independent of the mode of its application, whereas the elimination of quinidine was significantly increased after its s.c. application. Pretreatment of rats with aluminium chloride (600 mg/kg, i.p.) 2 h before injecting one of the stereoisomers had a different effect on their concentrations in blood, and significantly higher effect on their bile elimination. The quinine concentrations in blood after its p.o. administration were not changed significantly, but after s.c. application these concentrations were increased in some time intervals. The presence of the aluminum ion caused a significant increase in the rate of hepatic elimination of quinine, whereas it had no significant effect on quinidine elimination.

An extensive scrutiny of 19,460 patients' charts was carried out by clinical pharmacists in six Australian Repatriation Hospitals. The incidence of the prescribing of digoxin-quinidine and digoxin-amiodarone combinations was 0.18% and 0.22% of patients, respectively, giving an overall level of 0.4% (4/1000). For both combinations, digoxin was prescribed long term in 81% of the cases and quinidine or amiodarone recently added to digoxin therapy in 44% of patients identified. Therapeutic drug monitoring of digoxin therapy was initiated by clinical pharmacists in 41% of patients and resulted in modifications to digoxin therapy in 63% of this sub-group of patients. Quinidine and amiodarone therapies were also changed in nine patients. Of particular note was the number (15 or 58%) of dosage changes or therapy cessations made to digoxin therapy for patients also receiving amiodarone which occurred as a result of clinical pharmacist intervention.

The pharmacokinetics of quinidine in healthy subjects was studied through serum and salivary compartments by orally administering 250 mg of quinidine sulphate (CAS 50-54-4) either at 10:00 or 22:00 h. Quinidine concentrations in the biological samples were determined fluorimetrically. None of the pharmacokinetic parameters obtained from serum levels showed any significant time dependent changes. However, prolongation in tmax and lowering of Ka and t1/2 was noticed after nocturnal drug administration when the parameters were computed from salivary levels. Also, significant (p < 0.05) lowering of saliva/serum (SL/SR) ratios was observed after 22:00 h drug dosing. Temporal alterations in quinidine secretion into saliva could be the reason for the above changes. Alteration of salivary quinidine levels in turn could be caused by altered protein binding in serum and/or the time dependent changes in the permeability of biological membranes involved in the production of saliva.

Forty-one horses were treated for atrial fibrillation (AF) with 22 mg/kg quinidine sulfate via nasogastric tube every 2 hours until conversion to sinus rhythm, a cumulative dose of 88 to 132 mg/kg had been administered in 2-hour increments, or the horse had adverse or toxic effects from the drug. Treatment intervals were prolonged to every 6 hours if conversion had not occurred. Digoxin was administered before treatment if the horse had a fractional shortening < or = 27% (3 horses), was prone to tachycardia (resting heart rate > or = 60 beats/min) (1 horse), or had a previous history of sustained tachycardia of over 100 beats/min during prior conversion (3 horses). Digoxin was administered during day 1 of quinidine sulfate treatment if the horse developed a sustained tachycardia of over 100 beats/min during treatment (11 horses) or on day 2 if conversion had not occurred (7 horses). Plasma quinidine concentrations within 1 hour of conversion of AF to sinus rhythm ranged from 1.7 to 7.5 micrograms/mL (mean, 4.05 +/- 1.6) and ranged from 1.7 to 4.7 micrograms/mL in 97% of horses. Most horses (92%) with plasma quinidine concentrations > 5 micrograms/mL exhibited an adverse or toxic effect of quinidine sulfate (clinical or electrocardiographic). There was no statistical association between plasma quinidine concentrations and sustained tachycardia (> 100 beats/min), diarrhea, or colic. Ataxia and upper respiratory tract stridor were significantly associated with plasma quinidine concentrations. In most instances (98%) conversion did not occur while toxic or adverse effects of quinidine sulfate were present or when plasma quinidine concentrations were > 5 micrograms/mL.

A sensitive, specific, and rapid high-performance liquid chromatographic method with ultraviolet detection for therapeutic drug monitoring of the cardioactive compound quinidine is described. The method uses only 50 microliters of serum, which is extracted into methyl-t-butylether at an alkaline pH and consequently reextracted into dilute hydrochloric acid. Quinidine is separated from quinine, the internal standard, and dihydroquinidine on a reversed phase C18 column. The minimum detectable amount is 1 ng injected on column. The method is both precise and accurate, as shown by the validation data presented, and can also be of use in pharmacokinetic investigations.

Quinidine is a very potent inhibitor of CYP2D6, but the role of the enzyme in the biotransformation of quinidine has only been investigated in a single in vitro study and in two small in vivo experiments, with contradictory results. The present investigation was designed to present definite evaluation of whether quinidine is metabolised by CYP2D6. Eight poor metabolizers (PM) and 8 extensive metabolizers (EM) of sparteine each took one oral dose of 200 mg quinidine. In the EM, the total clearance, the clearance via 3-hydroxylation and the clearance via N-oxidation, were 33, 3.7 and 0.23 l.h-1, respectively. In the PM, the corresponding values were 29, 3.1 and 0.18 l.h-1, respectively. There were no statistically significant differences between EM and PM in any of these pharmacokinetic parameters. It is concluded that CYP2D6 is not an important enzyme for the oxidation of quinidine.

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.

In two hundred and twenty-five healthy volunteers not receiving any treatment the occurrence of drug-like factors in blood serum was studied. The examinations were carried out with the use of the fluorescence-polarization-immunoassay (FPIA)-TDx Abbott. The presence of endogenous phenytoin-like, theophylline-like and cyclosporin-like factors has been demonstrated.

High-performance liquid chromatography (HPLC) was used for the therapeutic drug monitoring of quinidine in clinical samples. Solid-phase extraction (SPE) was studied in both off-line and on-line modes. SPE was performed in an automatic on-line mode using a fully automated Prospekt system. Extraction recoveries were in the range 97.1-99.4% for 1-2 micrograms/ml quinidine concentrations. For HPLC separation an Ultrasep RP-8 reversed-phase column was applied with acetonitrile-water (9:1) containing 0.3% triethylamine (pH 2.5) as the mobile phase. The Prospekt system is recommended for the routine monitoring of quinidine in plasma samples. Concentrations were in therapeutic range (1.2-3.6 micrograms/ml).

High-performance liquid chromatographic methods that use direct injection of plasma include column-switching procedures, modified mobile phases and small-pore modified stationary phases. By using a large-pore (300 A) Selectosil C18 column, developed for the analysis of macromolecules, we have shown that quinidine in plasma and protein solutions can be assayed accurately and rapidly by directly injecting 2 microliters plasma or protein solution onto the column. Column life is not reduced, and the limit of quantitation is 0.01 microM.

The response to intravenous procainamide (15 to 20 mg/kg) and to oral quinidine 324 to 648 mg every 8 hours for 3 to 5 days was prospectively studied in 50 consecutive patients (43 men and 7 women, aged 38 to 83 years old [mean 64 +/- 11]) with coronary artery disease and baseline-inducible sustained monomorphic VT. Mean procainamide and trough quinidine serum levels were 10.5 +/- 2.6 and 2.6 +/- 0.8 micrograms/ml, respectively. Mean left ventricular ejection fraction was 37 +/- 12%. Sustained monomorphic VT was suppressed by intravenous procainamide in 18 patients (36%); 8 of these patients (44%) also had suppression with oral quinidine, but 10 (56%) did not. Of the 32 patients (64%) who continued to have inducibility with intravenous procainamide, 12 (38%) responded to oral quinidine and 22 (62%) did not. The overall concordant response rate to intravenous procainamide and oral quinidine was 56% (28 of 50 patients). It is concluded that the response (i.e., the presence or absence of inducible sustained monomorphic VT) to intravenous procainamide does not adequately predict the response to oral quinidine in patients with coronary artery disease and sustained monomorphic VT.

The effects of two antiarrhythmic agents, hydroquinidine and quinidine on the prevention of pacing induced sustained ventricular tachycardia (VT) were studied in 14 patients. The underlying cardiac disease was old myocardial infarction (12 patients) or dilated cardiomyopathy (2 patients). Sustained monomorphic VT was induced in 14 patients during the initial electrophysiological study performed at least 48 hours after withdrawal of all antiarrhythmic therapy. The same stimulation protocol including 3 extrastimuli (S2 S3 S4) and 2 paced cycles (600 ms and 400 ms) was repeated at least 48 hours after the administration of 600 mg (2 gelules) per 24 hours of hydroquinidine or 1100 mg of quinidine arabogalactane sulphate, 3 to 4 hours after the last dose. This was an open, randomised, crossed over trial. Irrespective of the result observed with the first antiarrhythmic, used in an order attributed by a randomised table, the other antiarrhythmic was tested. Plasma concentrations were measured during the programmed stimulation test for both drugs. Induced VT was prevented by the two antiarrhythmics in 4 patients (28%). In one patient, VT was prevented by hydroquinidine but not by the quinidine compound, resulting in a prevention rate of 35% for the hydroquinidine. On the other hand, the quinidine compound was a total success in one patient in whom only a partial success was observed with hydroquinidine. VT remained inducible with both antiarrhythmics in 9 patients (64%).(ABSTRACT TRUNCATED AT 250 WORDS)

Fourteen patients with supraventricular and/or ventricular ectopic beats selected by clinical, dynamic ECG and exercise test, underwent a basal continuous ECG recording (Holter) and then were given 400 mg of quinidine orally. The concentrations of the drug were determined in blood samples taken 30 minutes before, and 1, 2, 4, 6, 8, 12, and 24 hours after administration. On the same day patients were also monitored by continuous ECG recording (Holter). One week later, after a washout period, the same subjects were treated with 200 mg of quinidine orally 4 times a day for two weeks. On day 1, 2, 4, 7 and 14 quinidine was determined in plasma, and on day 7 and 14 a 24 hour ECG recording was also done. On the basis of pharmacokinetic parameters obtained from the acute test, the chronic levels of the drug were predicted. Predicted values were superimposable to those observed. Thus, the kinetics of single-dose quinidine is able to predict the steady-state levels after repeated dosing. During acute administration there was an increase in QTc interval and a decrease in ectopic beats. These effects correlated with a sigmoid pattern with acute quinidine levels. Concentrations producing 50% of the effect (EC50) could be calculated from these curves. In spite of similar steady-state blood levels of quinidine, some patients after chronic therapy did not respond to treatment (non responders). Non responders could be predicted by the acute test because they had greater EC50 values of QTc increase: patients with EC50 greater than 2 mg/L were all non responders.

A new simple, selective and reproducible high-performance liquid chromatographic method for the determination of quinine in plasma, saliva and urine is described. The ion-pair method was carried out on a reversed-phase C18 column, using perchlorate ion as the counter ion and ultraviolet detection at 254 nm. Quinine was well resolved from its major metabolite, 3-hydroxyquinine, and the internal standard, primaquine. The limit of detection was 10 ng/ml and the recovery was greater than 90% from the three biological fluids.

1. Eight healthy Thai males, aged 19-27 years, received quinine or quinidine dihydrochloride 10 mg kg-1 body weight by intravenous infusion over 1 h. At least 1 week later, the alternative alkaloid was administered. 2. The terminal elimination half-time of quinidine was shorter than that of quinine (median [range]; 5.7 [5.0-10.0] vs 9.9 [8.8-15.1] h, P < 0.01), the volume of distribution at steady state (Vss) for quinidine was larger than that for quinine (3.5 [2.5-5.6] vs 3.1 [1.8-4.1] 1 kg-1; P = 0.02) and quinidine was less bound to plasma proteins (% free drug: 22.8 [15.4-47.2] vs 9.4 [7.3-15.0]%, P < 0.01). Total clearance was greater for quinidine (7.7 [3.9-11.4] vs 3.4 [1.8-4.6] ml min-1 kg-1, P < 0.01) but not for clearance of unbound drug (32.2 [14.6-50.4] vs 29.9 [20.2-50.9] ml min-1 kg-1 respectively, P > 0.2). 3. Side-effects, including transient hypotension after quinidine in two cases, were mild. 4. Both drugs produced prolongation of the rate-corrected QT interval (QTc), with similar rates of elimination from the cardiac conduction 'effect' compartment (keo; 4.14 [0.03-15.33] h-1 for quinine, 3.74 [1.63-13.14] h-1 for quinidine, P > 0.19). Using a linear concentration-response model, the intercept ('threshold') for quinidine effect was lower than that for quinine (P = 0.004) but the slopes (change in QTc for a given change in free drug concentration) were similar (P = 0.56).(ABSTRACT TRUNCATED AT 250 WORDS)

Quinidine-like immunoreactivity (Abbott TDx Quinidine fluorescence polarization immunoassay) was measured in control, sham-operated, abdominal aorta stenotic and hyperthyroid (thyroxine feeding 0.1 mg/rat/day rats. The mean quinidine levels (mumol quinidine/1 serum) were 0.07, 0.14, 0.13 and 0.25, respectively. The elevation in experimental hyperthyroidism was statistically (analysis of variance, Duncan's test) significant. The possibility of the existence of an endogenous antiarrhythmic, immunologically cross-reacting in quinidine immunoassay, is discussed.

The effect of the increased plasma protein binding of quinidine on its disposition was investigated in turpentine-treated rats, since turpentine treatment is known to increase the plasma concentration of alpha 1-acid glycoprotein which preferentially binds basic drugs. The plasma free fraction of quinidine 16 and 48 h after turpentine treatment was decreased by 30 and 76%, respectively, compared to the control value. The treatment did not cause liver injury nor alter the hepatic blood flow. The disappearance of quinidine in plasma after an intravenous injection (3.0, 7.0, 12.5 mg/kg) was analyzed by a two-compartment open model in both control and turpentine-treated rats. The blood total body clearance (CLb) of quinidine at 48 h after the treatment was decreased by 30 to 65% in a dose-dependent manner, compared to that in control rats. The distribution volume (Vdss) of quinidine (12.5 mg/kg) at 16 and 48 h after turpentine treatment was decreased by 30 and 79%, respectively. Hepatic extraction ratio (HER) of quinidine, which was determined at steady state blood concentrations from 0.5 to 2.3 micrograms/ml, was decreased from 0.8 to 0.35 with an increase in the quinidine concentration in control rats. The HER value 48 h after turpentine treatment was consistently reduced by 15 to 40% in a concentration-dependent manner compared to the corresponding control value. These findings indicate that the increased plasma binding of quinidine caused a reduction of HER of the drug, and the reduced HER resulted in the decrease in CLb in turpentine-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

The electrophysiologic and hemodynamic effects of H 234/09 (Almokalant), a novel class II antiarrhythmic agent, were studied in the anesthetized dog. H 234/09 (1.0 mumol/kg i.v.) significantly prolonged the atrial and ventricular effective refractory periods, the ventricular monophasic action potential duration, and the paced QT interval. At this dose, atrial, ventricular, and atrioventricular conduction was not affected, aortic blood pressure was not changed, and contractile force was transiently increased. The effects on cardiac repolarization and refractoriness induced by H 234/09 were both larger and more long lasting than the effects observed after quinidine (11.8 mumol/kg) and (+)-sotalol (9.7 mumol/kg). However, both quinidine and (+)-sotalol significantly reduced the aortic blood pressure and (+)-sotalol also decreased cardiac contractility. The effect of H 234/09 on atrial refractoriness was very little influenced by the paced heart rate and was twice as large as the corresponding effect in the ventricle. In conclusion, H 234/09 has electrophysiological properties suggestive of a class III antiarrhythmic. H 234/09 may have a favorable therapeutic profile compared to both quinidine and (+)-sotalol, especially for the treatment of atrial arrhythmias.