R. Dahlqvist

Inhibition of desipramine 2‐hydroxylation by quinidine and quinine

Urinary excretion of desipramine (DMI) and 2‐hydroxydesipramine (2‐OH‐DMI) after single oral doses of 25 mg DMI was investigated in seven rapid and three slow debrisoquin hydroxylators, before and after pretreatment with either quinidine or its diastereoisomer quinine. After treatment with 800 mg quinidine daily for 2 days, excretion of 2‐OH‐DMI decreased by 96% in rapid hydroxylators and 68% in slow hydroxylators. After treatment with 750 mg quinine/day for 2 days, excretion of 2‐OH‐DMI in rapid hydroxylators was 54% lower than during the control experiment, whereas in slow hydroxylators no significant changes in the excretion pattern were observed. Unchanged DMI constituted only a minor fraction of recovered drug and no significant changes in its recovery were observed in either phenotypic group after pretreatment with quinidine or quinine. Thus both quinidine and quinine decreased the excretion of 2‐OH‐DMI. At similar doses the effect of quinidine was much stronger than that of quinine, virtually transforming rapid hydroxylators into slow hydroxylators. The mechanism probably involves a stereoselective inhibition of DMI 2‐hydroxylation.

Interactions in the renal and biliary elimination of digoxin : stereoselective difference between quinine and quinidine

The interactions between digoxin and quinine and quinidine that affect the renal and biliary clearances of digoxin were investigated in eight healthy subjects. Digoxin (0.5 to 0.75 mg/day) was given alone and with concomitant administration of quinine (750 mg/day) to reach a steady‐state level. In four of the subjects, the study was repeated by administration of equimolar doses of the diastereoisomer quinidine together with digoxin, enabling a within‐subject comparison of the effects of the two isomers on digoxin clearance. The biliary excretion of digoxin was studied by use of a modified duodenal marker perfusion technique. A marked reduction was found in the steady‐state biliary clearance of digoxin from control value 134 ± 57 ml/min (mean ± SD) to 87 ± 39 ml/min during treatment with quinine (p < 0.05) and from 95 ± 24 to 55 ± 27 ml/min during treatment with quinidine (p < 0.01; n = 4). Quinidine reduced the renal clearance of digoxin (155 ± 26 versus 110 ± 21 ml/min) (p < 0.05; n = 4), whereas quinine had no such effect (177 ± 40 versus 185 ± 53 ml/min; not significant). These findings explain the difference in magnitude between quinidine and quinine in regard to the interaction with digoxin and imply a different degree of stereoselectivity for these isomers in the renal and biliary secretory systems of digoxin.

Digoxin-verapamil interaction: Reduction of biliary but not renal digoxin clearance in humans

The interaction between digoxin and verapamil was studied in six patients (mean age ± SD, 61 ± 5 years) with chronic atrial fibrillation. The effects of adding verapamil (240 mg/day) on steady‐state plasma concentrations and renal and biliary clearances of digoxin were studied in a crossover manner. The biliary clearance of digoxin was determined by a duodenal perfusion technique. Verapamil induced a 44% increase in steady‐state plasma concentrations of digoxin, from 0.80 ± 0.24 to 1.15 ± 0.40 nmol/L (p < 0.01). The biliary clearance of digoxin decreased by 43%, from 187 ± 89 to 101 ± 55 ml/min (p < 0.05), in the presence of verapamil, whereas the renal clearance was unaffected (153 ±31 versus 173 ± 51 ml/min; difference not significant). Our results indicate that the main inhibitory effect of verapamil on digoxin elimination is on the biliary route.

Quinidine reduces biliary clearance of digoxin in man.

Abstract. Quinidine is known to reduce the renal clearance of digoxin, but this effect does not completely explain the influence of quinidine on the total clearance of digoxin. We therefore studied the effect of quinidine administration on biliary clearance of digoxin in five patients with atrial fibrillation. Biliary clearance of digoxin under steady state conditions before and during treatment with quinidine was investigated using a duodenal‐marker‐perfusion technique. Quinidine caused an average 42% (range 21–65%, P < 0·02) reduction of the measured biliary clearance of digoxin. We conclude that the biliary effect adds to the previously demonstrated inhibitory effect of quinidine on the renal clearance of digoxin and helps to explain the decrease in total clearance of the drug. This is the first demonstration in man of a pharmacokinetic drug interaction at the level of biliary excretion.

Effect of quinidine on digoxin concentration in skeletal muscle and serum in patients with atrial fibrillation. Evidence for reduced binding of digoxin in muscle.

QUINIDINE causes a rise in serum steady-state concentrations of digoxin1 2 3 4 5 and reduces both renal and nonrenal clearances of digoxin.6 7 8 A redistribution of digoxin from tissue stores was s...

Comparative class 1 electrophysiologic and anticholinergic effects of disopyramide and its main metabolite (mono-N-dealkylated disopyramide) in healthy humans.

SummaryDuring steady-state treatment with disopyramide, its main and active metabolite, mono-N-dealkylated disopyramide, was reported to reach concentrations that were equal to or higher than the parent drug in 25% of 70 evaluated patients. This metabolite has been found to have a more pronounced anticholinergic action than the parent drug on in vitro evaluation, but neither its anticholinergic nor its direct electrophysiologic effects on the human heart have been properly assessed. We therefore compared the acute electrophysiologic and anticholinergic effects (the standard being atropine, 0.04 mg/kg) of disopyramide and its main metabolite, given 2 mg/kg body weight intravenously to 10 healthy individuals in a double-blind, randomized, crossover design. The anticholinergic effect of these substances on sinus and atrioventricular node function was unexpectedly found to be of similar magnitude and more pronounced than previously thought (at least one-third the effects of the atropine dose). The class 1 electrophysiologic effects were as follows: intraatrial and His-Purkinje conduction (the PA and the HV interval, respectively) was prolonged 33% (95% CI: 18–47%) and 27% (21–32%) by disopyramide, and 15% (10–19%) and 13% (10–17%), respectively, by the metabolite. Disopyramide also prolonged the QRS, JT, and QT intervals by 15% (9–21%), 10% (8–13%), and 10% (7–12%), respectively. The metabolite caused a 9% (7–12%) prolongation of the QRS interval (significantly less than disopyramide), but shortened repolarization (as reflected by the JT interval) by -7% (-2 to -11%; p<0.01), which is similar to the acute effects of lidocaine 2 mg/kg body weight. As a result the maximal effect on spontaneous QT and QT after atrial pacing was a shortening of -5% to -6% (p<0.01). The metabolite thus has both class 1A and 1B effects. Due to the different electrophysiologic effects of disopyramide and its main metabolite, their concentration ratio may in individual patients have considerable importance for the clinical effects on atrial and/or ventricular arrhythmias, as well as for arrhythmogenic propensity and other adverse reactions. The potential of the metabolite as an antiarrhythmic agent deserves further evaluation.

Digoxin-interactions in man: Spironolactone reduces renal but not biliary digoxin clearance

SummaryThe possibility of an inhibitory effect of spironolactone on the biliary clearance of digoxin has been investigated in 6 healthy subjects.Plasma clearance and the renal and biliary clearance of digoxin were determined twice at steady state (digoxin 0.5 to 1 mg·d−1 p.o. for 6 days), alone or in combination with spironolactone 200 mg daily, after an intravenous dose of digoxin (0.7 × oral dose) on Day 7. Plasma and urine were collected for 48 h. Biliary clearance of digoxin was determined on Day 8 by a duodenal perfusion technique.During spironolactone treatment plasma digoxin clearance tended to be lower (255 vs 224 ml/min; P=0.057) and renal clearance significantly lower (166 vs 144 ml/min), while the biliary clearance of digoxin remained unchanged (106 vs 103 ml/min).Thus, spironolactone reduced the renal clearance of digoxin by an average of 13%, without affecting its biliary clearance.

Cardiac Effects of Treatment With Quinidine and Digoxin, Alone and in Combination

Systolic time intervals (QS2-I and LVET-I) and echocardiographically determined ejection fraction and velocity of circumferential fiber shortening were recorded in 10 healthy volunteers as measures of inotropic effect during maintenance treatment with 4 consecutive drug regimens: (1) quinidine, 1,200 mg/day; (2) digoxin, average dose 0.31 mg/day; (3) the combination of (1) and (2); and (4) digoxin alone (average dose 0.65 mg/day) to provide the same steady-state serum concentration of digoxin as during the period with combination of digoxin and quinidine. The steady-state serum concentration of digoxin during the low-dose regimen increased from 0.72 +/- 0.15 (mean +/- standard deviation [SD]) to 1.63 +/- 0.28 nmol/liter when quinidine was added. With the high dose of digoxin alone, the serum digoxin level reached 1.68 +/- 0.50 nmol/liter. Skeletal muscle digoxin concentrations during these periods were 27.7 +/- 8.3, 48.7 +/- 16.2, and 51.6 +/- 23.6 nmol/kg of dry weight, respectively. The skeletal muscle to serum concentration ratio of digoxin decreased significantly during quinidine treatment. Systolic time intervals were significantly prolonged by quinidine alone and shortened by digoxin alone, the latter effect being dose-dependent. Subtracting the effect of quinidine itself, the induced increase in digoxin level caused a significant increase in inotropic effect. When these corrected values were compared with those attained during the period with the same steady-state digoxin concentration but in the absence of quinidine, no significant differences were found. Echocardiographically measured ejection fraction and velocity of circumferential fiber shortening showed trends for similar drug effects, as did the systolic time intervals. This study, performed under steady-state conditions, demonstrates that the quinidine-induced increase in steady-state serum digoxin concentration will, with due consideration to quinidines own pharmacodynamic properties, be accompanied by increased cardiac effects. This indicates that quinidine is not interfering with active receptor sites in the heart for digoxin.

Quinidine-induced changes in serum and skeletal muscle digoxin concentration; evidence of saturable binding of digoxin to skeletal muscle

SummaryEleven patients with atrial fibrillation on maintenance digoxin therapy were investigated by analysis of serum (SDC) and skeletal muscle (SMDC) digoxin concentrations before and 24 h and 2 weeks after starting quinidine treatment. After cardioversion the maintenance dose of digoxin was reduced in order to obtain the same steady-state SDC after 2 weeks, as before quinidine. SDC was increased by quinidine therapy from 1.56 to 2.40 nmol/1 after 24 h. With the reduced digoxin dose SDC was 1.68 nmol/1 after 2 weeks. The ratio SMDC/SDC decreased after 24 h of quinidine treatment from 35.4 to 29.0 (p<0.01). After 2 weeks of quinidine treatment with the reduced digoxin dose, the ratio had risen to 38.1, which did not differ significantly from the initial ratio. The present data suggest that the reduced skeletal muscle binding of digoxin during quinidine therapy is due to saturation of digoxin binding sites secondary to the increase in the total body load of digoxin at steady-state, and not to direct interference by quinidine with digoxin binding sites.

Enantioselective steady-state kinetics of unbound disopyramide and its dealkylated metabolite in man

SummaryDisopyramide is provided as a racemic mixture of R and S enantiomers, which have different pharmacodynamic and pharmacokinetic characteristics. Five volunteers were given racemic disopyramide 100 mg and 200 mg t.d.s. in a cross-over design. Plasma and urine concentrations of disopyramide and its active metabolite monodesisopropyl-disopyramide (MND) were determined at steady state by an enantioselective HPLC method. Unbound drug in plasma was measured after ultrafiltration.There was enantioselective clearance of unbound disopyramide (0.39 l.h−1.kg−1 for R-disopyramide and 0.58 l.h−1.kg−1 for S-disopyramide after 100 mg t.d.s.). The enantioselectivity was due to differences in the metabolism of disopyramide to MND and in further non-renal clearance, and the renal clearance of disopyramide was not enantioselective.The in vivo protein binding of disopyramide, which was saturable for both enantiomers, was also enantioselective. The difference in binding of the two enantiomers was explained by a difference in apparent binding capacity rather than in apparent binding affinity.The renal clearance of S-MND was significantly higher than R-MND (0.29 and 0.19 l.h−1.kg−1, respectively, after 100 mg t.d.s.). The renal clearance of MND also showed a tendency to saturation at higher concentrations.