The effect of digoxin dosage on the digoxin-quinidine interaction in the bile duct-cannulated rat

Pretreating anaesthetized bile duct-cannulated rats with 9 mg kg-1 quinidine significantly decreased the cumulative biliary excretion of digoxin and its metabolites after 10 or 100 micrograms kg-1 [3H]digoxin, although the effect was more marked in animals receiving the high dose of digoxin. In contrast, however, although quinidine pretreatment raised plasma radioactivity levels by 50-80% in animals given the higher dose of digoxin, no significant effect on circulating plasma levels was observed in rats receiving 10 micrograms kg-1 digoxin. Generally, quinidine had no statistically significant effect on other aspects of digoxin disposition, although with both digoxin doses there were trends towards a reduction in the direct intestinal secretion and urinary excretion of digoxin-derived radioactivity with an increase in tissue levels of radioactivity (apart from the small intestine wall where concentrations were reduced). The radioactivity in the bile after 100 or 10 micrograms kg-1 digoxin comprised about 25 and 33% of digoxin and digoxigenin bis-digitoxoside, respectively, as well as appreciable amounts of the monodigitoxoside and a highly polar component. This metabolite profile was unaffected by quinidine. The influence of cardiac glycoside dosage shown by the present work indicates that the digoxin-quinidine interaction and possibly analogous interactions involving other cardiac glycosides, may not always be readily detectable from plasma concentration data.     

The relationship between cardiotoxicity and plasma digoxin concentration in conscious dogs.

1 The tendency of a given oral dose of digoxin to induce cardiac dysrhythmia was determined indirectly at various times after its administration to eight conscious dogs by measurement of the intravenous dose of acetylstrophanthidin necessary to induce toxic changes in the ECG. Acetyl-strophanthidin was used because its rapid elimination from the body permitted estimates to be made 45, 180 and 360 min after digoxin administration. 2 Each dog underwent four studies in which doses of 0.05, 0.1, 0.2 and 0.4 mg/kg digoxin were used in a randomized sequence allowing at least ten days between each dose. 3 Digoxin reduced the amount of acetylstrophanthidin required to cause toxic changes in the ECG; this increase in cardiac sensitivity was dose-dependent. 4 There was no correlation between plasma levels of digoxin and the tendency to dysrhythmia, since peak plasma concentrations of digoxin were reached at about 60 min after dosing whereas maximal sensitivity to acetylstrophanthidin was found 3 to 6 h after administration of digoxin. 5 These results suggest that there is little or no increased risk of cardiotoxicity during periods of transient increase in plasma levels of digoxin.     

Disposition of radiolabeled ifetroban in rats, dogs, monkeys, and humans.

Ifetroban is a potent and selective thromboxane receptor antagonist. This study was conducted to characterize the pharmacokinetics, absolute bioavailability, and disposition of ifetroban after i.v. and oral administrations of [14C]ifetroban or [3H]ifetroban in rats (3 mg/kg), dogs (1 mg/kg), monkeys (1 mg/kg), and humans (50 mg). The drug was rapidly absorbed after oral administration, with peak plasma concentrations occurring between 5 and 20 min across species. Plasma terminal elimination half-life was approximately 8 h in rats, approximately 20 h in dogs, approximately 27 h in monkeys, and approximately 22 h in humans. Based on the steady-state volume of distribution, the drug was extensively distributed in tissues. Absolute bioavailability was 25, 35, 23, and 48% in rats, dogs, monkeys, and humans, respectively. Renal excretion was a minor route of elimination in all species, with the majority of the dose being excreted into the feces. After a single oral dose, urinary excretion accounted for 3% of the administered dose in rats and dogs, 14% in monkeys, and 27% in humans, with the remainder excreted in the feces. Extensive biliary excretion was observed in rats with the hydroxylated metabolite at the C-14 position being the major metabolite observed in rat bile. Ifetroban was extensively metabolized after oral administration. Approximately 40 to 50% of the radioactivity in rat and dog plasma was accounted for by parent drug whereas, in humans, approximately 60% of the plasma radioactivity was accounted for by ifetroban acylglucuronide.     

Lack of acipimox-digoxin interaction in patient volunteers.

1. A study was carried out to find out if digoxin and acipimox interact. 2. Six elderly patients on digoxin were each given acipimox 150 mg three daily for a week, after informed consent. Digoxin and acipimox plasma concentrations and urinary excretion were measured after the first dose of acipimox and after a week of treatment. 3. Data were fitted to a one-compartment oral absorption model. Areas under the plasma concentration-time curve, plasma and renal clearances, and elimination half-life were computed. 4. There was no significant difference in digoxin plasma concentrations and kinetic parameters before and after acipimox administration. Acipimox kinetics were not affected by the concomitant ingestion of digoxin. 5. The patients' clinical condition remained stable during the study. 6. Thus there was no evidence for an adverse interaction between digoxin and acipimox in human subjects under the conditions of this study.     

Metabolic disposition of Rolziracetam in laboratory animals

The metabolic disposition of [14C]-labeled Rolziracetam (CI-911) was studied in rhesus monkeys, beagle dogs, and Wistar rats after both p.o. and i.v. doses. Intravenously administered CI-911 was rapidly eliminated from systemic circulation with an apparent elimination half-life of less than 25 min. Plasma radioactivity was 10-20 times higher than that of parent drug and persisted much longer. After oral doses, only traces of intact drug were detected in plasma, whereas total radioactivity reached peak concentrations within 0.5-1 h indicating rapid absorption. The extent of absorption determined from plasma radioactivity and urinary excretion data was 90% or better. Tissue distribution of radioactivity in rats showed the highest concentrations in the liver and kidneys (12-30 times greater than plasma levels) with decreasing levels in the lungs, gonads, heart, spleen, muscle, and brain. Urinary excretion accounted for nearly 90% of the administered dose while fecal recovery was less than 5%. The sole metabolite present in plasma, tissues, and urine was identified as 5-oxo-2-pyrrolidinepropanoic acid (PD 106,687).     

The plasma disposition and renal elimination of digoxin-specific Fab fragments and digoxin in the rabbit.

Administering digoxin-specific antibody fragments (DSFab, 1.9 mg kg-1, i.v.) to rabbits 1 h after digoxin (15 micrograms kg-1 or 12.5 microCi kg-1, i.v.) produced a redistribution of digoxin associated with a 5-fold elevation in total plasma concentration and 36-86% reductions in elimination half-life, apparent volume of distribution at steady-state and total body clearance (CLT). Renal clearance (CLR) was also reduced (54%), but urinary digoxin excretion was increased by one-third (35% vs 25%). This apparent anomaly is due to the large rise in total plasma digoxin concentration with a consequent increase in the area under the plasma concentration curve (AUC). The AUC, which is the denominator term in calculating CLR (and CLT), was increased to a greater extent than urinary digoxin excretion (numerator term in calculating CLR) so that an overall reduction in CLR occurred. The initial presence of digoxin appeared to alter the distribution of DSFab, since their plasma concentrations were markedly higher when the antibody was given after the hapten. The digoxin also reduced (from 3 to 1%) the amount of detectable DSFab in the urine.     

Pharmacokinetics of digoxin-specific Fab: effects of decreased renal function and age

Aims To study the influence of age and renal function on digoxin-specific Fab (DS-Fab) pharmacokinetics.
Methods Sixteen patients (35–91 years) with creatinine clearance ranging from 10.6 to 122.1  ml  min⁻¹ who had been admitted to hospital with severe digoxin or digitoxin self-poisoning were treated with DS-Fab (80 to 800  mg). Plasma DS-Fab concentrations were determined by radioimmunoassay.
Results The mean (±s.d.) distribution and elimination half-lives, apparent volume of distribution and total body clearance were 1.1±0.4  h, 20.2±7.3  h, 13.1±5.8  l, and 17.6±10.8  ml  min⁻¹ , respectively. Interindividual variability of DS-Fab total body clearance was linked linearly with the decrease in creatinine clearance or with the increase in age and DS-Fab distribution volume was not dependent on creatinine clearance or age.
Conclusions The data suggest that DS-Fab should be given to elderly and renal-impaired patients at doses similar to those given to younger or normal renal function patients.     

Identification of an N-Oxide as the Major Metabolite of the Analgesic O-(Diethylaminoethyl)-4-Chlorobenz-aldoxime Hydrochloride in Dogs

1. After oral administration to dogs of the analgesic O-(diethylaminoethyl)-4-chloro[7-¹⁴C]benzaldoxime hydrochloride together with piperazine hydro-chloride (2:1, w/w), at a dose of 4.5?mg/kg, the radioactivity was well absorbed and rapidly excreted. During 5 days, 81% of the dose (ca. 50% in 12?h) was excreted in urine and 10% in faeces.

2. Rates and routes of excretion of radioactivity were not altered in animals pre-treated with the drug for fourteen days.

3. Peak mean plasma concentrations of radioactivity (5.5 μg equiv./ml) occurred at 90 min after an oral dose and were higher than those at 2 min following an equivalent intravenous (3.4 μg equiv. /ml) or rectal (4.0 μg equiv. /ml) dose which gave a max. at 45?min.

4. The drug was rapidly and extensively metabolized and no unchanged drug was detected in the plasma or urine. The major urinary metabolite was the N-oxide of the parent compound accounting for 34% and 23% dose excreted in the urine of males and females respectively during 12?h after administration.     

Disposition and metabolism of ralfinamide, a novel Na-channel blocker, in healthy male volunteers

Ralfinamide is an α-aminoamide derivative with ion channel blocking properties, acting both peripherally and centrally through different molecular targets important in pain control. Absorption, blood and plasma time courses, and urinary and faecal excretion of total radioactivity were assessed in 6 male healthy volunteers administered a single oral dose of 320 mg 1?C-(S)-ralfinamide. Pharmacokinetics of the parent drug were investigated over 120 h, urinary and plasma metabolites up to 192 h post-dose. 1?C-(S)-ralfinamide was rapidly and completely absorbed. Ralfinamide and the dealkylated ralfinamide metabolite (NW-1716) represented the majority of plasma radioactivity. Plasma elimination of the parent compound occurred mono-exponentially (half-life approx. 15 h). 1?C-radioactivity was eliminated in a bi-phasic manner (terminal half-life of 60 and 24 h for plasma and whole blood, respectively). Plasma-concentrations of unchanged ralfinamide were significantly lower than radioactivity concentrations, indicating metabolism of the parent compound. At 192 h post-dose the total balance of radioactivity was almost complete (95%). The main route of excretion was via the kidneys (94% of the dose). Major metabolites identified in urine and plasma were the N-dealkylated acid of ralfinamide and deaminated ralfinamide acid (NW-1799). Other metabolites, in particular the product of glucuronide conjugation N-dealkylated-β-glucuronide, were identified.     

Metabolism and pharmacokinetics of nufenoxole in animals and humans: an example of stereospecific hydroxylation of an isoquinuclidine ring

1. Nufenoxole, a novel antidiarrhoeal agent, was well absorbed in rat, monkey and human after oral administration. Systemic availability of nufenoxole was 85% in monkey and 102% in man. 2. The elimination rate was much faster in rat (t1/2 of 1.8 h) and monkey (t1/2 of 4.9 h) compared with human (t1/2 of 35.8 h). 3. After oral and i.v. 14C-nufenoxole, concentrations of 14C in human erythrocytes and saliva were approx. 3- and 4-fold lower, respectively, than plasma concentrations. 4. Nufenoxole was metabolized to metabolites hydroxylated on the methyl substituent and isoquinuclidine ring in rat and monkey. The isoquinuclidine ring hydroxylation, a major pathway in human, was stereospecific. 5. Following oral doses of 14C-nufenoxole the urinary excretion of radioactivity (about 8%) was less than the faecal excretion (66.6%) in rat, while urinary excretion was the major route of drug elimination (about 60%) in man. In monkey, urinary and faecal excretion were equally important.     

Pharmacokinetics of tritiated ouabain, digoxin and digitoxin in guinea-pigs

1. Elimination rates of tritiated ouabain, digoxin and digitoxin after single intravenous administrations were investigated in guinea-pigs, the total radioactivity in whole blood being traced for a period of up to 2 weeks. 2. In the initial rapid phase of elimination between 2 and 30 min following intravenous glycoside administration, the concentration decline of radioactivity in the blood was found to be identical for the three glycosides investigated, this part of the elimination curve displaying a hyperbolic shape. 3. During this early elimination phase, rapid metabolic degradation and excretion of digoxin had already taken place. The maximum concentration of radioactivity in the bile was reached 4 min following intravenous administration of 3H-digoxin. The positive inotropic response occurred in the cat heart-lung preparation 1.5 min after intravenous injection of a therapeutic dose of digoxin, indicating a quick occupation of binding sites in the tissues. 4. The biological half-lives of tritiated ouabain, digoxin and digitoxin averaged 11 h, 2.5 days and 4.1 days, respectively, as determined by the terminal exponential elimination phase, in guinea-pigs. This terminal phase was attained 6-12, 7-24, and 24-48 h after administration of ouabain, digoxin and digitoxin, respectively. 5. The findings reveal that in guinea-pig, as has been demonstrated in man, the elimination rates of the three glycosides increase according to their hydrophobic properties. 6. The biological half-lives of tritiated ouabain, digoxin and digitoxin obtained in the guinea-pig closely resemble those found in healthy man.     

Effect of rofecoxib on the pharmacokinetics of digoxin in healthy volunteers

The authors examined the effect of the cyclooxygenase-2 (COX-2) inhibitor, rofecoxib, at steady state on the pharmacokinetics of digoxin following a single dose in healthy subjects. Each healthy subject (N = 10) received rofecoxib (75 mg once daily) or placebo for 11 days in a double-blind, randomized, balanced, two-period crossover study. A single 0.5 mg oral dose of digoxin elixir was administered on the 7th day of each 11-day period. Each treatment period was separated by 14 to 21 days. Samples for plasma and urine immunoreactive digoxin concentrations were collected through 120 hours following the digoxin dose. No statistically significant differences between treatment groups were observed for any of the calculated digoxin pharmacokinetic parameters. For digoxin AUC(0-infinity), AUC(0-24), and Cmax, the geometric mean ratios (90% confidence interval) for (rofecoxib + digoxin/placebo + digoxin) were 1.04 (0.94, 1.14), 1.02 (0.94, 1.09), and 1.00 (0.91, 1.10), respectively. The digoxin median tmax was 0.5 hours for both treatments. The harmonic mean elimination half-life was 45.7 and 43.4 hours for rofecoxib + digoxin and placebo + digoxin treatments, respectively. Digoxin is eliminated renally. The mean (SD) cumulative urinary excretion of immunoreactive digoxin after concurrent treatment with rofecoxib or placebo was 228.2 (+/- 30.8) and 235.1 (+/- 39.1) micrograms/120 hours, respectively. Transient and minor adverse events occurred with similar frequency on placebo and rofecoxib treatments, and no treatment-related pattern was apparent. Rofecoxib did not influence the plasma pharmacokinetics or renal elimination of a single oral dose of digoxin.     

Assessment of the potential pharmacokinetic interaction between digoxin and ethmozine

The potential for a pharmacokinetic interaction between the investigational antiarrhythmic drug ethmozine (moricizine HCl, the generic name that is infrequently used in existing literature) and digoxin was evaluated in nine healthy male adults. Serum and urinary digoxin concentrations were measured by radioimmunoassay following intravenous digoxin administration before and during steady-state ethmozine dosing. Plasma ethmozine levels following a single oral dose were measured before and after a single intravenous dose of digoxin. A mean elimination half-life of 45.6 hours was determined for digoxin alone, compared to 43.1 hours in combination with ethmozine. Average values for digoxin systemic clearance, apparent volume of distribution, and renal clearance were 2.87 mL/min/kg, 11.3 L/kg, and 2.44 mL/min/kg, respectively for digoxin alone, compared to 3.01 mL/min/kg, 11.3 L/kg, and 2.64 mL/min/kg, respectively for digoxin with ethmozine. A mean half-life of 2.0 hours was determined for ethmozine alone, compared with 1.8 hours following a single intravenous dose of digoxin. No change was observed in the oral pharmacokinetics of ethmozine following a single intravenous dose of digoxin, as indicated by the area under the plasma concentration versus time curve, Cmax or Tmax. These findings suggest that no pharmacokinetic interaction occurs when single intravenous doses of digoxin are co-administered with multiple oral doses of ethmozine.     

The disposition and metabolism of [14C]fluconazole in humans.

The disposition and metabolism of 14C-labeled fluconazole (100 microCi) was determined in three healthy male subjects after administration of a single oral capsule containing 50 mg of drug. Blood samples, total voided urine, and feces were collected at intervals after dosing for up to 12 days post-dose. Pharmacokinetic analysis of fluconazole concentrations showed a mean plasma half-life of 24.5 hr. Mean apparent plasma clearance and apparent volume of distribution were 0.23 ml/min/kg and 0.5 liter/kg, respectively. There was no evidence of any significant concentrations of metabolites circulating either in plasma or blood cells. Mean total radioactivity excreted in urine and feces represented 91.0 and 2.3%, respectively, of the administered dose. Mean excretion of unchanged drug in urine represented 80% of the administered dose; thus, only 11% was excreted in urine as metabolites. Only two metabolites were present in detectable quantities, a glucuronide conjugate of unchanged fluconazole and a fluconazole N-oxide, which accounted for 6.5 and 2.0% of urinary radioactivity, respectively. No metabolic cleavage products of fluconazole were detected.     

The disposition and metabolic fate of 14C-cibenzoline in man

The disposition and metabolic fate of cibenzoline (CBZ) following single oral 153-mg doses of 14C-CBZ succinate were studied in five healthy adult males. The mean maximum plasma radioactivity of 386 ng eq/ml occurred at 2.4 hr after administration. The mean half-life, determined from the 14C plasma concentration and urinary excretion rate data, was 13.1 and 14.8 hr, respectively. The mean maximum CBZ concentration was 196 ng/ml at 1.2 hr post-dose. The mean half-life, determined from the plasma concentration and urinary excretion rate data, was 7.2 and 7.3 hr, respectively. The mean total clearance of radioactivity and CBZ was 300 ml/min and 1224 ml/min, respectively, due to elimination via both renal and nonrenal pathways. The only unconjugated metabolite in the plasma was 4,5-dehydrocibenzoline which, together with other unidentified metabolites, is presumed responsible for the longer observed half-life for total radioactivity. Approximately 75% of the dose was recovered in the urine in the first 24 hr after dosing, 80% of which was present at CBZ and known metabolites. After 6 days, a mean of 85.7% of the dose was excreted in urine and 13.2% in feces. The predominant excreted compound was CBZ (55.7% of the dose) in the 0-72 hr urine. Although several metabolites were identified in urine samples, none were found in substantial amounts relative to the parent drug. Two of these substances showed slight antiarrhythmic activity, whereas the 4,5-dehydro metabolite, representing approximately 4% of radioactivity in urine, was inactive.     

Effect of spironolactone on excretion of 3H-digoxin and its metabolites in rats

Spironolactone increased the total excretion of radioactivity in female rats given specific labelled ³H-digoxin. This increase was due to enhanced fecal excretion while urinary elimination of radioactivity and blood tritium levels were reduced. The ratio of total excreted digoxin to its metabolites which was measured by paper and thin-layer chromatography was changed from 28%: 72% under control conditions to 2% : 98% during spironolactone treatment. This increased excretion of metabolites mainly concerned the aqueous soluble compounds, the digoxigenin monodigitoxoside and the digoxigenin. The excretion of the genin was enhanced in urine only.After metabolism of ³H-digoxin could still be observed 25 days after discontinuation of treatment with spironolactone. It is concluded that in rats spironolactone increased the metabolism of digoxin by induction of hepatic microsomal enzyme activity.     

Pharmacokinetics, distribution and excretion of YM155 monobromide, a novel small-molecule survivin suppressant, in male and pregnant or lactating female rats

YM155 monobromide is a novel small-molecule survivin suppressant. The pharmacokinetics, distribution and excretion of YM155/[14C]YM155 were investigated using males and pregnant or lactating female rats after a single intravenous bolus administration. For the 0.1, 0.3 and 1 mg/kg YM155 doses given to male rats, increases in area under the plasma concentration-time curves were approximately proportional to the increase in the dose level. After administering [14C]YM155, radioactivity concentrations in the kidney and liver were highest among the tissues in both male and pregnant rats: e.g. 14.8- and 5.24-fold, respectively, and higher than in plasma at 0.1 h after dosing to male rats. The YM155 concentrations in the brain were lowest: 25-fold lower than in plasma. The transfer of radioactivity into fetuses was low (about 2-fold lower than in plasma). In lactating rats, the radioactivity was transferred into milk at a level 8- to 21-fold higher than for plasma. Radioactivity was primarily excreted in feces (64.0%) and urine (35.2%). The fecal excretion was considered to have occurred mainly by biliary excretion and partly by secretion across the gastrointestinal membrane from the blood to the lumen.     

The effect of immunization with digoxin-specific antibodies on digoxin disposition in the mouse

After intravenous dosing, digoxin was rapidly distributed to tissues, with a distribution half-life of 3.0 min. The highest digoxin concentrations at 1 hr post dosing were found in lymph nodes, adrenals, gallbladder (including contents), liver and kidney respectively. Digoxin concentrations in the heart, spleen, brain, lung, skeletal muscle and fat were similar to, or lower than, those in the plasma. The apparent volume of distribution (AVd) was 11/kg, and the plasma elimination half-life and clearance (Cl) 2.8 hr and 0.251/kg per hr respectively. When digoxin was given one day after passive immunization with digoxin-specific immunoglobulin G (IgG) or Fab fragments the respective plasma digoxin concentrations were elevated some 26- and 5-fold respectively compared with control values. Consequently there were reductions in AVd (93 and 32%) and Cl (94 and 50%). The effect of IgG treatment on clearance was still apparent when the hapten was given up to 14 days after immunization, while the weaker effect of Fab-treatment was less persistent. Although tissue digoxin concentrations were slightly lower in the immunised mice, it was only in the lymph nodes at 10 and 14 days after IgG treatment that the reduction in hapten concentration was statistically significant.     

Pharmacokinetics of Cefixime in Children with Urinary Tract Infections after a Single Oral Dose

Abstract: The pharmacokinetics of cefixime, a third-generation broad-spectrum cephalosporin, were determined following administration of a 8 mg/kg single oral dose of cefixime suspension to six children with urinary tract infections, ages from 6 to 13 years and weights from 17 to 60 kg. Blood samples for determination of plasma cefixime concentrations were obtained for up to 12 hr and complete urine collections were obtained for urinary excretion of unchanged parent drug for up to 24 hr after administration. Plasma and urine concentrations of cefixime were determined using a reversed phase HPLC assay and pertinent pharmacokinetic parameters were estimated by model-independent standard methods. Mean peak plasma concentration was 4.04 ug/ml and was reached after 3.2 hr. The mean area under the plasma concentration-time curve was 33.07 ug.hr/ml and the mean elimination half-life was 3.91 hr. The mean apparent total clearance was 4.74 ml/min./kg and about 15% of the dose administered was recovered unchanged in urine. In conclusion, the estimated pharmacokinetic values of cefixime were comparable to those observed in healthy adult subjects based on equivalent mg/ kg doses. Plasma and urine concentrations of the drug were well above the reported minimal plasma and urinary concentrations for most common urinary tract pathogens for up to 12 and 24 hr after administration, respectively.     

Identification of an N-oxide as the major metabolite of the analgesic O-(diethylaminoethyl)-4-chlorobenzaldoxime hydrochloride in dogs

1. After oral administration to dogs of the analgesic O-(diethylaminoethyl)-4-chloro[7-14C]benzaldoxime hydrochloride together with piperazine hydrochloride (2:1, w/w), at a dose of 4.5 mg/kg, the radioactivity was well absorbed and rapidly excreted. During 5 days, 81 percent of the dose (ca. 50 percent in 12 h) was excreted in urine and 10 percent in faeces. 2. Rates and routes of excretion of radioactivity were not altered in animals pre-treated with the drug for fourteen days. 3. Peak mean plasma concentrations of radioactivity (5.5 microgram equiv./ml) occurred at 90 min after an oral dose and were higher than those at 2 min following an equivalent intravenous (3.4 microgram equiv./ml) or rectal (4.0 microgram equiv./ml) dose which gave a max. at 45 min. 4. The drug was rapidly and extensively metabolized and no unchanged drug was detected in the plasma or urine. The major urinary metabolite was the N-oxide of the parent compound accounting for 34 percent and 23 percent dose excreted in the urine of males and females respectively during 12 h after administration.