Acceleration of digoxin clearance by activated charcoal

The effect of repeated oral doses of activated charcoal on intravenous digoxin kinetics was evaluated in a randomized, crossover study. Ten healthy subjects received infusions of 10 micrograms/kg digoxin alone and with 225 gm activated charcoal over 40 hours. Multiple serum digoxin concentration determinations were made after each dose by radioimmunoassay. Noncompartmental kinetic analysis was used. Digoxin clearance increased an average of 47% (range -2% to 119%) during charcoal treatment, from 12.2 +/- 2.0 to 18.0 +/- 2.9 L/hr. The volume of distribution at steady state decreased from 495 +/- 196 to 375 +/- 162 L, and the terminal t1/2 was shortened from 36.5 +/- 11.8 to 21.5 +/- 6.5 hr during charcoal treatment. Likewise, mean residence time decreased, from 41.1 +/- 20 to 19.9 +/- 7.8 hr. Kinetic predictions would suggest greater proportional increases in digoxin clearance in patients with renal impairment. We conclude that repeated doses of charcoal enhance the clearance of digoxin and should be considered for use in digoxin toxicity.     

Effect of nifedipine on serum digoxin concentration and renal digoxin clearance

Nifedipine has been reported either to decrease or not to affect digoxin elimination. We studied the effect of oral nifedipine on steady-state digoxin concentrations and renal clearance in 20 healthy male subjects. After 2 wk of digitalization, all received digoxin, 0.375 mg a day, with placebo for 2 wk, then digoxin and nifedipine, 18.5 +/- 4 mg every 8 hr, for 2 wk, and then digoxin with placebo for 2 wk. Mean (+/- SD) digoxin concentrations of 0.74 +/- 0.20 and 0.75 +/- 0.25 ng/ml on placebo were not altered by nifedipine (0.77 +/- 0.23 ng/ml). Digoxin clearance was 2.2 +/- 0.6 and 2.7 +/- 0.8 ml/kg/min on placebo and 2.5 +/- 0.6 ml/kg/min on nifedipine. No change in pharmacologic effect of digoxin by nifedipine was observed, but mean blood pressure was lower and heart rates were accelerated. These data indicate that oral nifedipine does not alter digoxin concentrations or decrease renal clearance in healthy subjects.     

Hemoperfusion removal of digoxin from dogs

Removal of digoxin by XAD-4 hemoperfusion columns was tested after four dogs were given 0.06 mg/kg of digoxin i.v. Dogs were perfused for 4 to 5 hr at a flow of 105 ml/min through a 100 gm XAD-4 column 16 hr after the dose. Pharmacokinetic analysis of digoxin levels was performed with a three-compartment model. The apparent postdistribution t1/2 was 16.0 +/- 2.9 (S.D.) hr and decreased to 7.1 +/- 2.1 hr during perfusion. Digoxin perfusion clearance was 46 ml/min. An average of 51 microgram of digoxin was recovered from used columns. CP of digoxin calculated from the total R was 127.5 +/- 13 ml/min or 2.3 times greater than plasma flow. With the use of 3H-digoxin, canine blood was found to contain 2.5 times as much digoxin as did plasma. After perfusion there was an increase in serum digoxin levels in all dogs. Computer analysis showed that the increase in plasma digoxin levels immediately after hemoperfusion occurred because the central compartment, which was depleted of digoxin during hemoperfusion, was refilled from peripheral compartments. This study demonstrated that (1) XAD-4 hemoperfusion doubles the rate of removal of digoxin from dogs, (2) dog whole blood contains more than twice as much digoxin than does plasma, so that hemoperfusion clearance exceeds plasma flow, and (3) a multicompartmental pharmacokinetic model explains the increase in serum digoxin concentrations observed at the completion of hemoperfusion.     

Oral bioavailability of digoxin is enhanced by talinolol: evidence for involvement of intestinal P-glycoprotein

OBJECTIVE: Recent data indicated that disposition of oral digoxin is modulated by intestinal P-glycoprotein. The cardioselective beta-blocker talinolol has been described to be secreted by way of P-glycoprotein into the lumen of the gastrointestinal tract after oral and intravenous administration. We therefore hypothesized that coadministration of digoxin and talinolol may lead to a drug-drug interaction based on a competition for intestinal P-glycoprotein. METHODS: Pharmacokinetics of digoxin (0.5 mg orally), talinolol (30 mg intravenously and 100 mg orally), and digoxin plus talinolol orally, as well as digoxin plus talinolol intravenously, were assessed in five male and five female healthy volunteers (age range, 23 to 30 years; body weight, 60 to 95 kg) in a changeover study with at least a 7-day washout period. Digoxin and talinolol were analyzed by fluorescence polarization immunoassay and HPLC, respectively. RESULTS: Oral coadministration of 100 mg talinolol increased the area under the concentration-time curve (AUC) from 0 to 6 hours and the AUC from 0 to 72 hours of digoxin significantly by 18% and 23%, respectively (5.85+/-1.49 versus 7.22+/-1.29 ng x h/mL and 23.0+/-3.3 versus 27.1+/-3.7 ng x h/mL, for both P<.05) and the maximum serum levels by 45%. Renal clearance and half-life of digoxin remained unchanged. Coinfusion of 30 mg talinolol with oral digoxin had no significant effects on digoxin pharmacokinetics. Digoxin did not affect the disposition of talinolol after both oral and intravenous administration. CONCLUSION: We observed a significantly increased bioavailability of digoxin with oral coadministration of talinolol, which is most likely caused by competition for intestinal P-glycoprotein.     

Vascular binding, blood flow, transporter, and enzyme interactions on the processing of digoxin in rat liver

The roles of vascular binding, flow, transporters, and enzymes as determinants of the clearance of digoxin were examined in the rat liver. Digoxin is metabolized by Cyp3a and utilizes the organic anion transporting polypeptide 2 (Oatp2) and P-glycoprotein (Pgp) for influx and excretion, respectively. Uptake of digoxin was found to be similar among rat periportal (PP) and perivenous (PV) hepatocytes isolated by the digitonin-collagenase method. The Km values for uptake were 180 +/- 112 and 390 +/- 406 nM, Vmax values were 13 +/- 8 and 18 +/- 4.9 pmol/min/mg protein, and nonsaturable components were 9.2 +/- 1.3 and 10.7 +/- 2.5 microl/min/mg for PP and PV, respectively. The evenness of distribution of Oatp2 and Pgp was confirmed by Western blotting and confocal immunofluorescent microscopy. When digoxin was recirculated to the rat liver preparation in Krebs-Henseleit bicarbonate (KHB) for 3 h in absence or presence of 1% bovine serum albumin (BSA) and 20% red blood cell (rbc) at flow rates of 40 and 10 ml/min, respectively, biexponential decays were observed. Fitted results based on compartmental analyses revealed a higher clearance (0.244 +/- 0.082 ml/min/g) for KHB-perfused livers over the rbc-albumin-perfused livers (0.114 +/- 0.057 ml/min/g) (P < 0.05). We further found that binding of digoxin to 1% BSA was modest (unbound fraction = 0.64), whereas binding to rbc was associated with slow on (0.468 +/- 0.021 min(-1)) and off (1.81 +/- 0.12 min(-1)) rate constants. We then used a zonal, physiologically based pharmacokinetic model to show that the difference in digoxin clearance was attributed to binding to BSA and rbc and not to the difference in flow rate and that clearance was unaffected by transporter or enzyme heterogeneity.     

Effect of clarithromycin on steady-state digoxin concentrations

OBJECTIVE: To evaluate the magnitude and dose-relatedness of the effect of clarithromycin on the pharmacokinetics of digoxin, and to compare the effects of clarithromycin with those of P-glycoprotein inhibitors. METHODS: Eight Japanese inpatients with congestive heart failure participated in this study. Each patient received oral digoxin therapy for at least 7 days and were coadministered oral clarithromycin to prevent or treat pneumonia. To evaluate the effects of clarithromycin on the pharmacokinetics of digoxin, digoxin concentrations were compared before and after coadministration of clarithromycin. RESULTS: Digoxin concentrations were higher after coadministration of clarithromycin in all patients (before, 0.838 +/- 0.329 ng/mL; after, 1.36 +/- 0.619 ng/mL); (p < 0.005). A significant correlation was observed between the dose of clarithromycin and the percentage of increase in the digoxin concentration. CONCLUSIONS: Digoxin concentrations increased during concomitant administration of clarithromycin, and this effect was dose-dependent on clarithromycin. The percentage increase in digoxin concentrations after the usual oral dose of clarithromycin (400 mg/d) is approximately 70%. Therefore, digoxin concentrations must be monitored carefully after coadministration of clarithromycin, and the doses of digoxin may need readjustment in patients who are concomitantly receiving clarithromycin.     

Dipyridamole enhances digoxin bioavailability via P-glycoprotein inhibition

BACKGROUND: On the basis of in vitro studies indicating that dipyridamole is an inhibitor for the MDR1 efflux membrane transporter P-glycoprotein, we postulated that dipyridamole could increase the bioavailability of digoxin, a P-glycoprotein substrate. OBJECTIVES: The main objective was to determine whether dipyridamole alters the bioavailability of digoxin. The secondary objective was to determine whether the magnitude of the pharmacokinetic interaction was influenced by MDR1 genetic polymorphism in exon 26 (C3435T). Material and methods: (1) The effect of dipyridamole on in vitro P-glycoprotein-mediated, polarized transport of tritium-labeled digoxin was investigated in Caco-2 cell monolayers. (2) Twelve healthy volunteers participated in this open, randomized, 2-period crossover study, in which the effects of dipyridamole (300 mg/d for 3 days) versus placebo on the pharmacokinetics of a single oral dose of digoxin (0.5 mg) were compared. MDR1 genotyping (exon 26, C3435T) was determined before the study to include 6 homozygous CC and 6 homozygous TT subjects. RESULTS: Dipyridamole inhibited [(3)H]digoxin transport in Caco-2 cells with a 50% inhibitory concentration value of 1.5 +/- 1.5 micromol/L. We observed a 20% and 13% increase in digoxin area under the plasma concentration-time curve (AUC) from 0 to 4 hours and AUC from 0 to 24 hours (P <.05), respectively, during dipyridamole administration, which was consecutive to an increase in digoxin absorption. Digoxin AUC from 0 to 4 hours and AUC from 0 to 24 hours were significantly higher among subjects harboring the TT compared with the CC MDR1 genotype: 7.5 +/- 1.2 ng x h x mL(-1) versus 6.1 +/- 0.8 ng x h x mL(-1) and 20.2 +/- 2.1 ng x h x mL(-1) versus 16.8 +/- 1.7 ng x h x mL(-1), respectively (P <.05). Digoxin pharmacokinetic modifications during the dipyridamole period were similar in both genotypes. CONCLUSION: Dipyridamole is an in vitro and in vivo P-glycoprotein inhibitor that increases intestinal digoxin absorption and digoxin plasma concentrations. In light of the modest changes in digoxin pharmacokinetics in the presence of dipyridamole, this drug interaction is probably clinically irrelevant.     

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 less than 0.05) and from 95 +/- 24 to 55 +/- 27 ml/min during treatment with quinidine (p less than 0.01; n = 4). Quinidine reduced the renal clearance of digoxin (155 +/- 26 versus 110 +/- 21 ml/min) (p less than 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.     

阿奇霉素对地高辛血药浓度的影响

目的 探讨阿奇霉素对地高辛血药浓度的影响.方法长期口服地高辛且血药浓度稳定在0.5～2.0 ng/mL的心力衰竭患者316例,其中158例纳入试验组(口服或静脉滴注阿奇霉素),余下158例纳入对照组(未接受阿奇霉素治疗);酶放大免疫法测定试验组使用阿奇霉素前后的外周血地高辛浓度,并与对照组进行比较.结果 试验组患者在使用阿奇霉素5 d后地高辛血药浓度由(1.1±0.5)ng/mL升高至(1.5±0.5)ng/mL(P<0.05),大于2.0 ng/mL者13例(占8.2%);老年(≥60岁)患者地高辛浓度增高尤其明显(P<0.01).试验组地高辛浓度为(1.5±0.5)ng/mL,高于对照组的(1.1±0.3)ng/mL(P<0.05).结论 阿奇霉素可导致地高辛血药浓度升高,尤其是老年患者;应避免同时使用阿奇霉素和地高辛,减少毒性反应.     

Pharmacokinetic and pharmaceutic interaction between digoxin and Cremophor RH40

BACKGROUND: The pharmacokinetics of digoxin is modulated by the efflux pump P-glycoprotein. Cremophor EL (BASF Aktiengesellschaft, Ludwigshafen, Germany) (polyoxyl 35 castor oil), a castor oil derivative used to improve the solubilization of drugs and vitamins, has been shown to inhibit this membrane transporter in vitro and in vivo. So far, no study in humans has evaluated the effect of Cremophor RH40 (BASF Aktiengesellschaft) (polyoxyl 40 hydrogenated castor oil) on P-glycoprotein. METHODS: A randomized, double-blind, placebo-controlled crossover study in 12 healthy individuals was performed with a single oral dose of 0.5 mg digoxin in a hard gelatin capsule in combination with multiple doses of oral Cremophor RH40 (600 mg 3 times daily) or placebo. A digitized electrocardiogram with 12 standard leads was recorded to assess the pharmacodynamics of digoxin. RESULTS: Cremophor RH40 delayed and enhanced the absorption of digoxin in the first 5 hours after dosing. During Cremophor RH40 administration, digoxin lag time was significantly prolonged compared with placebo (0.53 +/- 0.25 hour versus 0.36 +/- 0.19 hour, P =.04). The peak concentration of digoxin increased by 22%, from 2.21 +/- 0.94 ng/mL to 2.69 +/- 1.28 ng/mL (P =.06). Similarly, the area under the plasma concentration-time curve from 0 to 5 hours significantly increased by 22% (5.23 +/- 1.63 h. ng/mL versus 4.30 +/- 1.12 h. ng/mL, P =.03). Digoxin did not cause a clinically significant change in the dynamic parameters during both periods. CONCLUSION: This study demonstrates a pharmacokinetic and pharmaceutic interaction between the emulgent Cremophor RH40 and digoxin, caused by P-glycoprotein inhibition and prolongation of the dissolution time of digoxin tablets by Cremophor RH40, respectively. Our in vivo study in humans supports the validity of in vitro observations on P-glycoprotein.     

Effect of Asian ginseng, Siberian ginseng, and Indian ayurvedic medicine Ashwagandha on serum digoxin measurement by Digoxin III, a new digoxin immunoassay

Asian ginseng, Siberian ginseng, and Indian Ayurvedic medicine Ashwagandha demonstrated modest interference with serum digoxin measurements by the fluorescent polarization immunoassay (FPIA). Recently, Abbott Laboratories marketed a new digoxin immunoassay, Digoxin III for application on the AxSYM analyzer. We studied potential interference of these herbal supplements on serum digoxin measurement by Digoxin III assay in vitro and compared our results with the values obtained by Tina-quant assay. Aliquots of drug-free serum pool were supplemented with various amounts of Asian ginseng, Siberian ginseng, or Ashwagandha approximating expected concentrations after recommended doses and overdoses of these herbal supplements in serum. Then digoxin concentrations were measured by the Digoxin III and Tina-quant (Roche Diagnostics) assay. We also supplemented aliquots of a digoxin pool prepared from patients receiving digoxin with various amounts of these herbal supplements and then measured digoxin concentrations again using both digoxin immunoassays. We observed modest apparent digoxin concentrations when aliquots of drug-free serum pool were supplemented with all three herbal supplements using Digoxin III assay (apparent digoxin in the range of 0.31-0.57 ng/ml), but no apparent digoxin concentration (except with the highest concentration of Ashwagandha supplement for both brands) was observed using the Tina-quant assay. When aliquots of digoxin pool were further supplemented with these herbal supplements, digoxin concentrations were falsely elevated when measured by the new Digoxin III assay. For example, we observed 48.2% (1.63 ng/ml digoxin) increase in digoxin concentration when an aliquot of Digoxin pool 1 (1.10 ng/ml digoxin) was supplemented with 50 microl of Asian ginseng extract (Brand 2). Measuring free digoxin does not eliminate the modest interferences of these herbal supplements in serum digoxin measurement by the Digoxin III assay.     

Salivary electrolytes and serum digoxin in the Assessment of digitalis intoxication (author's transl)]

Salivary electrolytes (potassium and calcium), as well as serum digoxin levels were measured in 114 patients receiving digoxin or one of its derivatives. The mean value of the product of salivary potassium (mVal/I) and calcium (mVal/i in digoxin-treated patients without signs of digitalis intoxication (group 1) was 235 +/- 137 (SD) and with digitalis intoxication (group 2) 404 +/- 161 (SD). The difference in these values was not of statistical significance. The mean serum digoxin levels were 1.38 +/- 0.6 ng/ml (SD) in group 1 and 2.97 +/- 0.7 ng/ml (SD) in group 2; this difference is highly significant (p less than 0.001). Both salivary electrolytes and serum digoxin levels were falsely elevated in 11% of group 1 patients. 50% of the cases in group 2 showed salivary electrolyte values within the range of group 1, but there was only 1 patient with a serum digoxin level of below 2 ng/ml. It can, thus, be concluded that measurement of the salivary electrolytes is a test of only limited value in the assessment of digitalis intoxication, whereas determination of the serum digoxin level is a valuable diagnostic tool.     

Role of human MDR1 gene polymorphism in bioavailability and interaction of digoxin,a substrate of P-glycoprotein

OBJECTIVE: Our objective was to quantitate the contribution of the genetic polymorphism of the human MDR1 gene to the bioavailability and interaction profiles of digoxin, a substrate of P-glycoprotein. METHODS: The pharmacokinetics of digoxin was studied in 15 healthy volunteers, who were divided into 3 groups (n = 5 each) on the basis of genotyping for the MDR1 gene, in a 4-dose study after single doses of digoxin alone (0.5 mg orally and intravenously) and coadministered with clarithromycin (400 mg orally for 8 days). The dose of digoxin was reduced during the clarithromycin phase (0.25 mg orally and intravenously). RESULTS: The bioavailability of digoxin in G/G2677C/C3435, G/T2677C/T3435, and T/T2677T/T3435 subjects were 67.6% +/- 4.3%, 80.9% +/- 8.9%, and 87.1% +/- 8.4%, respectively, and the difference between G/G2677C/C3435 and T/T2677T/T3435 subjects was statistically significant (P <.05). The MDR1 variants were also associated with differences in disposition kinetics of digoxin, with the renal clearance being almost 32% lower in T/T2677T/T3435 subjects (1.9 +/- 0.1 mL/min per kilogram) than G/G2677C/C3435 subjects (2.8 +/- 0.3 mL/min per kilogram), and G/T2677C/T3435 subjects having an intermediate value (2.1 +/- 0.6 mL/min per kilogram). Coadministration of clarithromycin did not consistently affect digoxin clearance or renal clearance. However, a significant increase in digoxin bioavailability was observed in G/G2677C/C3435 subjects (67.6% +/- 4.3% versus 85.4% +/- 6.1%; P <.05) but not in the other 2 genotype groups. CONCLUSION: The allelic variants in the human MDR1 gene are likely to be associated with altered absorption and/or disposition profiles of digoxin and P-glycoprotein-mediated drug interaction     

Effect of aging on the incidence of digoxin toxicity

OBJECTIVE: To evaluate the relationship of the therapeutic serum digoxin concentration (SDC) range (0.5-2 ng/mL, as recommended in previous clinical studies) with the incidence of digoxin toxicity during digoxin maintenance therapy. METHODS: Subjects included all inpatients (n = 462) and outpatients (n = 437) receiving digoxin oral maintenance therapy for heart failure and/or atrial fibrillation with tachycardia at Kosei Hospital, Anjo, Japan. SDC and blood chemistry analysis were determined, and a 24-hour Holter electrocardiographic recording was performed when the SDC was at the presumed steady-state concentration. RESULTS: Analysis of clinical data showed that there was an overlapping (toxic and nontoxic) range of SDCs in which the incidence of digoxin toxicity was patient-dependent (1.4-2.9 ng/mL). No patient exhibited signs or symptoms of digoxin toxicity when the SDC was <1.4 ng/mL; all patients had evidence of toxicity when the SDC was >3 ng/mL. Additionally, it was shown that the concentration range of this overlapping range tended to broaden and shift to lower concentrations with increasing age. Patients with signs of toxicity when their SDCs were in the overlapping range had normal serum creatinine, blood urea nitrogen, digoxin clearance, creatinine clearance, and potassium concentrations, except for a significantly higher mean age than patients without toxicity. The incidence of digoxin toxicity was dependent on increasing age in patients whose SDCs were within the recommended therapeutic range. Moreover, clinical evidence of digoxin toxicity in patients >71 years old was 26.5%, despite their SDCs falling between 1.4 and 2 ng/mL. CONCLUSIONS: Increased age is most likely associated with enhanced susceptibility to digoxin toxicity, possibly due to unknown pharmacodynamic changes. This raises the possibility that patients >71 years show clinical evidence of digoxin toxicity despite having SDCs within the recommended therapeutic range.     

Serum cystatin C level as a potentially good marker for impaired kidney function

OBJECTIVES: To evaluate the diagnostic significance of serum cystatin C levels in clinical practice. DESIGN AND METHODS: Serum (99m)Tc-DTPA clearance was compared with serum cystatin C, creatinine, beta(2)-microglobulin levels and creatinine clearance in a group of patients aged 42.61 +/- 7.55 years with glomerular filtration rates of 10-60 mL/min/1.73 m(2) (n = 52) and healthy controls aged 43.90 +/- 12.06 years (n = 52). RESULTS: No effect of sex on serum cystatin C levels was observed, but average levels increased with age. No significant difference was evident between the mean cystatin C levels of three blood samples taken at 1 month intervals from healthy subjects. Reference clearance was correlated with creatinine clearance (r = 0.957), cystatin C (r = 0.828), beta(2)-microglobulin (r = 0.767) and creatinine (r = 0.682). 60 mL/min/1.73 m(2) was chosen as the borderline for receiver-operating characteristics analysis. The values for the cut-off point, sensitivity, specificity and the area under curve were determined for cystatin C as 1.36 mg/L, 98%, 99% and 0.99 +/- 00.1, respectively; for creatinine, the values were 103 micromol/L, 80%, 100% and 0.97 +/- 0.01, respectively, and for beta(2)-microglobulin, the values were 2.51 mg/L, 86%, 92% and 0.94 +/- 0.02, respectively. CONCLUSION: Serum cystatin C level can be used as a marker for renal damage.     

Comparative effects of verapamil and isradipine on steady-state digoxin kinetics

The effects on the steady-state digoxin pharmacokinetics of verapamil (240 mg/day) and a new dihydropyridine calcium channel blocker, isradipine (15 mg/day), were compared. Nineteen healthy white men, aged 23 to 40 years, ingested 0.25 mg digoxin tablets every 12 hours for two consecutive periods of 2 weeks. Each subject also received one of the calcium channel blockers during one of these periods, with agent and sequence randomized. Analyst-blind RIA serum digoxin determinations demonstrated that the nine subjects who received isradipine, 5 mg t.i.d., had a small increment in peak digoxin level from 2.3 +/- 0.6 to 2.9 +/- 0.7 ng/ml (p less than 0.05) but no significant change in steady-state level or AUC over 12 hours. By contrast, the 10 subjects who received verapamil, 80 mg t.i.d., showed significant increases in steady-state (0.9 +/- 0.1 to 1.3 +/- 0.2 ng/ml; p less than 0.001) and peak serum digoxin concentrations (2.5 +/- 0.7 to 3.6 +/- 0.8 ng/ml; p less than 0.001) and in AUC (15.7 +/- 1.7 to 23.6 +/- 2.9 ng . hr/ml; p less than 0.001). Neither calcium channel blocker reduced renal digoxin clearance. Verapamil increases digoxin levels without affecting renal clearance. Isradipine has no clinically important interaction with digoxin.     

Renal function and digoxin clearance during quinidine therapy

Summary. To investigate further the handling of digoxin by the kidneys during quinidine therapy, clearances of digoxin, ⁵¹Cr-EDEA, PAH and endogenous creatinine were measured together with β₂-microglobulin in the urine before and during quinidine therapy in 10 patients on maintenance digoxin therapy. Renal clearance of digoxin (corrected for 30% plasma binding) decreased on the average by 55% (137 ± 73 to 73 ± 25 ml/min, mean ± SD). The steady state plasma concentration of digoxin increased more than twofold (1·0 ± 0·34 to 2·5 ± 0±79 nmol/l, mean ± SD). The clearances of ⁵¹Cr-EDTA and PAH were not altered during quinidine therapy, indicating that neither glomerular filtration nor total renal blood flow changed when quinidine was added. The ratio of the renal clearance of unbound digoxin to that of the glomerular filtration rate was above one for all 10 patients before quinidine, indicating the involvement of tubular secretion in the renal elimination of digoxin. After the administration of quinidine this ratio decreased in all patients (from 1·51 ± 0·30 to 0·83 ± 0·38, mean ± SD). Some patients had ratios well below one suggesting re-absorption of digoxin. β²-microglobulin excretion was unchanged during treatment with quinidine. It is concluded that a significant portion of the renal elimination of digoxin in man results from tubular secretion and that this excretory mechanism is inhibited by quinidine.     

Pharmacokinetic interaction of sparfloxacin and digoxin

Sparfloxacin, a broad-spectrum, oral fluoroquinolone antimicrobial agent, has a long elimination half-life that permits once-daily administration. Antibiotics may increase the oral bioavailability of digoxin, leading to increases in its plasma concentration. Since patients treated with sparfloxacin may be receiving concurrent treatment with digoxin, the possibility of an interaction between sparfloxacin and digoxin was examined in a double-masked, placebo-controlled, multiple-dose, two-way crossover study in 24 healthy male volunteers between 20 and 49 years of age. All subjects were given digoxin 0.3 mg once daily throughout the 20-day study. Sparfloxacin (or placebo) was given as a 400-mg loading dose on day 1, followed by single 200-mg daily doses for 9 days, with crossover to the alternate treatment on days 11 through 20. Plasma levels of digoxin were analyzed by validated radioimmunoassay, and plasma levels of sparfloxacin were analyzed by validated high-performance liquid chromatography. Concomitant administration of sparfloxacin and digoxin was generally well tolerated. Mean values for steady-state area under the concentration-time curve over 24 hours for the 2 treatments were virtually identical: 28.4 ng/h per mL(-1) for digoxin administered with placebo and 28.9 ng/h per mL(-1) for digoxin administered concomitantly with sparfloxacin. Mean steady-state maximum plasma concentrations were 3.91 and 3.59 ng/mL for digoxin with placebo and digoxin with sparfloxacin, respectively. Mean steady-state trough plasma digoxin concentrations for the 2 treatments were 0.87 and 0.89 ng/mL, respectively. Mean times to steady-state maximum plasma concentrations were identical at 0.89 hours for both treatments. Mean steady-state oral clearance was 10.6 L/h for digoxin alone and 10.4 L/h for digoxin with sparfloxacin. Thus administration of sparfloxacin in combination with digoxin did not alter the pharmacokinetics of digoxin in healthy male volunteers aged 20 to 49 years. Steady-state plasma sparfloxacin concentrations were consistent with those obtained in other multiple-dose phase I studies, suggesting that digoxin does not alter the steady-state pharmacokinetics of sparfloxacin.     

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 less than 0.01). The biliary clearance of digoxin decreased by 43%, from 187 +/- 89 to 101 +/- 55 ml/min (p less than 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.     

Digoxin intoxication: the relationship of clinical presentation to serum digoxin concentration

A radioimmunoassay for serum digoxin concentration has been used to study the interrelationships of circulating levels of the drug and various factors in the clinical setting in 48 hospitalized patients with cardiac rhythm disturbances due to digoxin intoxication. 131 patients on maintenance doses of digoxin without toxicity and 48 patients with equivocal evidence of digoxin excess were also studied and compared with the toxic group.Patients with cardiac rhythm disturbances due to digoxin intoxication tended to be older and to have diminished renal function compared with the nontoxic group; body weight, serum potassium concentration, underlying cardiac rhythm, and nature of cardiac disease were not significantly different for the groups as a whole. Despite comparable mean daily digoxin dosages, digoxin intoxicated patients had a mean serum digoxin concentration of 3.7 +/-1.0 (SD) ng/ml, while nontoxic patients had a mean level of 1.4 +/-0.7 ng/ml (P < 0.001), 90% of patients without evidence of toxicity had serum digoxin concentrations of 2.0 ng/ml or less, while 87% of the toxic group had levels above 2.0; the range of overlap between the two groups extended from 1.6 to 3.0 ng/ml. Patients with atrioventricular block as their principal toxic manifestation had a significantly lower mean serum digoxin concentration than those in whom ectopic impulse formation was the chief rhythm disturbance.Patients with equivocal evidence of digoxin excess had received comparable daily maintenance doses of digoxin but had a mean serum concentration of 1.9 +/-0.8 ng/ml, intermediate between those of the nontoxic (P < 0.005) and toxic (P < 0.001) groups. Renal function as judged by mean blood urea nitrogen concentration was also intermediate.The data indicate that knowledge of the serum digoxin concentration, weighed in the clinical context, is useful in the management of patients receiving this drug.