The comparative bioavailability of Lanoxin tablets and Lanoxicaps with and without sorbitol

Summary (1) The mean cumulative urinary digoxin excretion over 8 days was compared in 8 healthy volunteers after single doses of digoxin administered as 3 Lanoxin tablets of 0.25 mg, 3 digoxin tablets of 0.2 mg, 12 Lanoxicaps without sorbitol of 0.05 mg, 6 Lanoxicaps without sorbitol of 0.1 mg digoxin, 3 Lanoxicaps without sorbitol of 0.2 mg and 3 Lanoxicaps with sorbitol of 0.2 mg. (2) There was no significant difference between the 8 day cumulative urinary excretion for any of the Lanoxicaps treatments. (3) Cumulative urinary excretion after 3 digoxin tablets of 0.2 mg was significantly (P<0.05) lower than after all other treatments. (4) Cumulative urinary excretion after 3 Lanoxin tablets of 0.25 mg was not significantly different from that after any of the Lanoxicaps treatments except 0.1 mg Lanoxicaps without sorbitol, it was significantly (P<0.05) lower after the latter. (5) Mean urinary excretion of digoxin was 60% of ingested dose for all Lanoxicaps treatments and was significantly (P<0.05) higher than the mean value of 50% for both tablet treatments. (6) Enhanced absorption of digoxin from Lanoxicaps was confirmed and shown to be unrelated to the sorbitol content of the capsule shell.Trade marks     

The influence of digoxin particle size on absorption of digoxin and the effect of propantheline and metoclopramide.

1 The influence of particle size on absorption of digoxin was studied in ten healthy volunteers who received 0.5 mg digoxin as two standard Lanoxin tablets, or tablets containing micronized digoxin or large particle size digoxin. Tablets were given 30 min after 15 mg propantheline, 10 mg metoclopramine or a placebo tablet, and following an overnight fast. 2 The overall mean cumulative 4 day urinary excretion of digoxin was significantly lower (P less than 0.01) after large particle size digoxin than after standard or micronized digoxin. Mean cumulative urinary excretion following large particle size digoxin was reduced when administered after metoclopramide and increased after propantheline, the difference between these two treatments being significant (P less than 0.05). There was a significantly lower (P less than 0.05) overall mean cumulative excretion following standard by comparison with micronized digoxin. However, by comparison with placebo, neither metoclopramide nor propantheline significantly altered mean cumulative excretion after standard or micronized digoxin. Propantheline and metoclopramide affect absorption of digoxin from formulations of large particle size and slow dissolution rate only.     

Absolute bioavailability of digoxin tablets

Ten healthy male volunteers each received 0.5 mg digoxin orally and i.v. in a randomised, cross-over sequence with at least two weeks between doses. Plasma concentration and cumulative urinary excretion of digoxin were measured up to 6 and 144 h, respectively, after administration using a radioimmunoassay method. Absolute bioavailability (i.e. the percentage absorption from tablets compared to i.v. injection) was calculated by four methods: by comparing areas under plasma concentration/time curves (AUC) up to 6 h and to infinity, also by comparing cumulative urinary excretion up to 144 h (t max.) and to infinity. The mean of the two extrapolated values for the absolute bioavailability of digoxin (Sandoz) tablets is 78%.     

The pharmacokinetics of beta-methyl digoxin compared with digoxin tablets and capsules

Summary The intestinal absorption and urinary elimination rate of total cardioactive material was compared following digoxin and beta-methyldigoxin (BMD) administration to twelve healthy volunteers. Significantly more injected digoxin was recovered in urine. Urinary clearance was more rapid for digoxin, mean half-lives of elimination being 35 hours for digoxin and 40 hours for BMD. Calculated percentage intestinal absorption was lowest for digoxin tablets with a dissolution rate of 77% in one hour, intermediate for BMD tablets, and maximal for an experimental soft gelatin formulation of digoxin in solution. Respective mean values were 75%, 87% and 97%. Similar steady state plasma concentrations followed twice daily ingestion of the 0.25 mg digoxin tablets and 0.20 mg BMD tablets. Mean peak plasma concentration and percentage urinary recovery of ingested dose were higher during continued BMD administration. Between-subject variation in absorption was higher for the digoxin tablets. The comparative intestinal absorption of BMD and digoxin depends upon the formulation. Digoxin is virtually completely absorbed from a solution encapsulated in soft gelatin. Relatively more BMD is eliminated by nonrenal routes.     

The comparability of dosage regimens of Lanoxin tablets and Lanoxicaps.

1 Twice daily administration of 0.25 mg digoxin tablets (Lanoxin) or of 0.2 mg digoxin in solution in soft gelatin capsules (Lanoxicaps) produced similar mean steady state plasma digoxin concentrations in ten healthy volunteers. Respective values were 1.07 +/- 0.075 and 0.95 +/- 0.048 ng ml-1. 2 During continued administration, peak plasma concentrations occurred earlier after capsules with a tendency to higher peak levels. However, area under curve determinations over 7 h were similar. 3 Approximately 10% less digoxin was recovered in urine collected in a 12 h dosage interval during the lower dosage administration of capsules. Mean percentage urinary recovery of administered dose was 57% for tablets and 65% for capsules. 4 The enhanced bioavailability of Lanoxicaps was associated with reduced between-subject variability in plasma concentration. 5 Lanoxicaps (0.2 mg) should be approximately equivalent in effect to digoxin tablets (0.25 mg) currently available in the United Kingdom, though improved consistency would be anticipated.     

A Study of the Potential Pharmacokinetic Interaction of Lisinopril and Digoxin in Normal Volunteers

1.The pharmacokinetics of single oral doses of 20 mg lisinopril and 0.25 mg digoxin. given alone and together, have been studied in 12 normal young male volunteers.

2.Peak serum conc of lisinopril occurred at 6 to 8 h and were slightly higher during combined treatment. Subsequent elimination proceeded moderately rapidly in both cases. concn declining to approx. 25% of peak values in 24 h. The AUC of lisinopril was similarly slightly higher during combined treatment.

3.After lisinopril alone, urinary elimination of unchanged lisinopril was 13% dose in 72 h, and after combined therapy was 17% dose.

4.Although there were no statistically significant differences in lisinopril pharmacokinetics during single or combined treatment, serum and urinary parameters suggest that bioavailability may be enhanced slightly during combined treatment.

5.Plasma concentrations of digoxin were slightly lower and urinary excretion slightly higher during combined treatment, the mean renal clearance being 20% higher.     

Bioavailability of digoxin from rapidly dissolving preparations

1 Intestinal absorption of digoxin was assessed by determination of peak plasma concentrations, areas under plasma concentration curves over 80 h, and 10 day urinary excretion. Absorption was equal after ingestion of single doses of standard Lanoxin (Wellcome) tablets, tablets and capsules of ultra-rapid dissolution rate material, or an oral solution of digoxin in water.

2 Mean plasma concentrations and dosage-interval urinary excretion were highly similar during 14 day courses of either Lanoxin or ultra-rapid dissolution tablets. Increased bioavailability does not result from encapsulation of solid dosage presentations, nor from increasing tablet dissolution rate beyond 75% in 15 minutes.

3 Fourteen day courses of tablets of slow dissolution rate produced lower and less consistent mean plasma concentrations and urinary excretion. Slow dissolution rates are associated with greater individual variability in absorption.

     

Enhanced bioavailability of digoxin from silica matrix formulations (author's transl)]

The bioavailability of digoxin from 3 silica matrix formulations was assessed in single-dose crossover studies in 12 healthy human volunteers: digoxin/silica matrix tablets (I, Digacin), digoxin/silica matrix in capsule form (II) and digoxin/silica matrix dragées, protected against gastrict juice by film coating (III). Urinary glycoside excretion for 6 days after 0.5 mg doses were measured by radioimmunoasay. Referring to an intravenous injection the bioavailability of digoxin from Digacin tablets is 82%, from the encapsulated matrix 69%, and from the dragées 54%. In comparison with corresponding results from other investigators Digacin tablets havet the same high bioavailability as digoxin solutions. In vitro liberations of digoxin from the silica matrix formulations (94% in 90 s) is significantly better than from conventional tablets produces from a digoxin-lactose trituration (61% in 90 s).     

Tolerability and serum levels of benoxaprofen in healthy volunteers

Tolerability, serum levels and urinary excretion of benoxaprofen (B) in therapeutic doses of 400 or 600 mg as a capsule were studied in 22 healthy volunteers after single or multiple doses. B was determined by a HPLC procedure. Apart from a skin reaction in one patient, no major problems were encountered by patients. Mean serum peak values after 400 and 600 mg were 49.84 and 94.54 micrograms/ml respectively. Mean time to peak was 5.6 hours and mean half-life ranged between 45.38 (400 mg regimen) and 63.48 hours (600 mg regimen). Urinary excretion was only a fraction of the doses ingested: 14.39% after a single dose; 35.5% after multiple doses. This may depend on other pathways of elimination of the drug because steady state is reached according to half-life.     

Effect of multiple doses of montelukast, a CysLT1 receptor antagonist, on digoxin pharmacokinetics in healthy volunteers.

The effect of multiple oral doses of montelukast, a cysLT1 receptor antagonist, on the pharmacokinetics of oral digoxin was studied in healthy male volunteers in a randomized double-blind two-period crossover study. Subjects received 10 mg of montelukast or placebo daily for 11 days. On day 7, they received a single 0.5 mg oral dose of digoxin elixir. The pharmacokinetic parameters of digoxin (AUC0-->24' AUC0-->infinity' Cmax' tmax' t1/2) and cumulative urinary excretion over 120 hours were not affected by the multiple doses of montelukast. The 90% confidence interval for each of these parameters fell within prespecified clinically acceptable bounds. Side effects were mild and transient. This suggests that concurrent administration of montelukast and digoxin was well tolerated. Concurrent treatment with montelukast has no effect on the pharmacokinetics of digoxin.     

Effect of multiple doses of losartan on the pharmacokinetics of single doses of digoxin in healthy volunteers.

1. Losartan (DuP 753, MK-954) is a novel, potent and highly selective AT1 angiotensin II receptor antagonist. The effect of multiple oral doses of losartan on digoxin pharmacokinetics was evaluated in healthy male subjects. 2. In a double-blind and randomized fashion, subjects received 50 mg losartan or placebo once daily for 15 days in each period. At least 7 days elapsed between the two treatment periods. On days 4 and 11 of each period, subjects also received a single 0.5 mg dose of digoxin intravenously and orally respectively. 3. Eleven of 13 subjects completed the study. Side effects were mild and transient (12 out of 13 subjects reported at least one adverse experience). During the study, no laboratory abnormalities were noted. 4. Multiple oral doses of losartan (50 mg daily) did not affect the pharmacokinetic parameters of 0.5 mg of digoxin i.v. AUC(0.48h) of immunoreactive digoxin during losartan 28.8 +/- 2.9 vs 28.5 +/- 3.9 ng ml-1 h during placebo; not significant, and 96 h urinary excretion [% dose] during losartan 54.0 +/- 7.2 vs 51.9 +/- 6.5% during placebo; not significant). Geometric mean ratios (90% confidence interval) for AUC and urinary excretion were respectively, 1.03 (0.98, 1.08) and 1.09 (0.98, 1.21). 5. Multiple oral doses of losartan did not affect the pharmacokinetic parameters of oral digoxin AUC(0.48 h) during losartan 23.6 +/- 3.7 ng ml-1 h vs 22.4 +/- 2.6 ng ml-1 h during placebo; not significant, Cmax 3.5 +/- 0.7 ng ml-1 with vs 3.1 +/- 0.5 ng ml-1 without losartan; not significant and tmax 0.6 +/- 0.2 h with vs 0.9 +/- 0.7 h without losartan; not significant, and 96 h urinary excretion [% dose] during losartan 51.2 +/- 6.3 vs 46.3 +/- 2.4% during placebo; not significant). Geometric mean ratios (90% confidence interval) for AUC and urinary excretion were respectively, 1.06 (0.98, 1.14) and 1.12 (0.97, 1.28). 6. We conclude that multiple oral doses of losartan (50 mg daily) do not alter the pharmacokinetics of immunoreactive digoxin, following either intravenous or oral digoxin. Furthermore, the co-administration of digoxin with losartan is well tolerated by healthy male volunteers.     

Bioavailability of digoxin tablets in healthy volunteers

The bioavailability of digoxin generic tablets manufactured in Korea (formulations A & B) were compared to a standard (formulation C; Lanoxin brand digoxin, Burroughs Wellcome, USA) in 12 healthy Korean male volunteers (mean age 31.4 years) in a single dose, randomized, complete block crossover study. Using a Latin square design, each of the subjects was randomized to the order number and allocated to each of the three treatments of 0.5 mg oral digoxin. Digoxin concentrations in serum and urine samples collected for 48 hours after dosing were measured by fluorescence polarization immunoassay and radioimmunoassay, respectively. Treatments were compared by using nonlinear least squares regression analysis to evaluate the following pharmacokinetic parameters: maximum serum concentration (Cmax); time of maximum serum concentration (Tmax); area under the serum concentration-time curve for 0-12 hours (AUC0-12); and cummulative urinary excretion for 0-48 hours (CUE0-48). Mean AUC0-12, Cmax, and CUE0-48 values for formulations B and C were significantly different from formulation A (p < 0.001), but not significantly different from each other. Based on AUC0-12 and CUE0-48, respectively, the relative availability of formulation B was 87.5% and 89.6% and the relative availability of formulation A was 43% and 35% when compared to formulation C (the standard).     

Effect of magnesium--aluminum hydroxide and kaolin--pectin on absorption of digoxin from tablets and capsules

Twelve healthy fasting volunteers received two 0.2-mg digoxin capsules or tablets with 60 ml water, 60 ml Maalox, or 60 ml Kaopectate in a randomized, single-dose, six-way crossover study. Concentrations of digoxin in multiple plasma samples and in all urine collected during the 24 hours after each dose were determined by radioimmunoassay. Compared to the water treatment, administration of both tablets and capsules with Maalox or Kaopectate reduced the peak digoxin plasma concentrations but did not significantly influence the time of peak concentration. Neither Maalox nor Kaopectate influenced the area under the 24-hour plasma concentration--time curve for either tablets or capsules. However, 24-hour urinary recovery of digoxin from tablets tended to be reduced by Maalox and Kaopectate; this was not the case with capsules. Digoxin capsules may have an advantage over currently available tablets in clinical situations requiring digoxin coadministration with nonabsorbable gastrointestinal preparations.     

A study of the potential pharmacokinetic interaction of lisinopril and digoxin in normal volunteers

1. The pharmacokinetics of single oral doses of 20 mg lisinopril and 0.25 mg digoxin, given alone and together, have been studied in 12 normal young male volunteers. 2. Peak serum conc of lisinopril occurred at 6 to 8 h and were slightly higher during combined treatment. Subsequent elimination proceeded moderately rapidly in both cases, concn declining to approx. 25% of peak values in 24 h. The AUC of lisinopril was similarly slightly higher during combined treatment. 3. After lisinopril alone, urinary elimination of unchanged lisinopril was 13% dose in 72 h, and after combined therapy was 17% dose. 4. Although there were no statistically significant differences in lisinopril pharmacokinetics during single or combined treatment, serum and urinary parameters suggest that bioavailability may be enhanced slightly during combined treatment. 5. Plasma concentrations of digoxin were slightly lower and urinary excretion slightly higher during combined treatment, the mean renal clearance being 20% higher.     

Glucuronidation of amitriptyline in man in vivo

The urinary excretion of amitriptyline (AT) as N-glucuronide was studied in healthy volunteers after single oral doses of AT and in patients on continuous treatment with AT. In the volunteers, 8 +/- 3% of a 25 mg dose of AT was recovered in urine as glucuronide during 108 hr. No difference between slow and rapid debrisoquine hydroxylators with respect to the excretion of AT glucuronide was seen. 0.08 to 1.68% of the given AT dose was recovered in urine in unchanged form. The excretion of unchanged AT correlated with the debrisoquine metabolic ratio (rs = 0.61; p less than 0.01). In 5 patients on continuous treatment with AT (125-150 mg/day), 8 +/- 5% of the daily dose was recovered in 24-hr urine as AT glucuronide. The present study shows that direct glucuronidation is a minor metabolic pathway of AT in man in vivo both after single low doses and during continuous treatment with therapeutic doses.     

Bioavailability and Pharmacokinetics of a New Sustained-Release Potassium Chloride Tablet

The bioavailability of a new sustained-release potassium chloride (KC1) tablet, designed for once-a-day dosing, was compared to a KC1 elixir using urinary excretion data. The study utilized 25 male volunteers dosed in a crossover design in a dietary/activity-controlled environment. The regimens consisted of a total of 80 mEq of potassium in three equally divided doses of elixir every 6 hr and a single 80-mEq dose using four 20-mEq sustained-release (SR) tablets. The mean time to maximum rate of potassium urinary excretion was 2.2 hr for the first elixir dose and 5.5 hr after the SR tablet (P < 0.01), thereby supporting the prolonged-release properties of this formulation. After correction for baseline urinary potassium excretion, the mean total 24-hr urinary potassium excretion was 42.18 mEq for the elixir and 40.41 mEq for the SR tablet. The results indicate that the absorption pattern from the SR tablet is equal to three doses of KC1 elixir dosed 6 hr apart.     

Effect of Repeated Doses of Hydroflumethiazide on Renal Excretion of Electrolytes and Uric Acid in Healthy Subjects

Abstract: Urinary excretion of electrolytes and uric acid was investigated in six healthy subjects during repeated oral administration of 100 mg hydroflumethiazide (HFT) daily for seven days, and related to urinary thiazide excretion. Mean 24 hr-urinary excretion of sodium and chloride increased 100% (P<0.02) after the first HFT-dose, whereas 24 hr-excretion values were at control level after the fourth and seventh doses. Mean 24 hr-urinary excretion of potassium was increased by 31% after the first HFT-dose (P<0.05) and by 47% after the fourth dose (P <0.05). After HFT was discontinued, mean urinary excretion rates of sodium and chloride dropped to 30% and that of potassium to 70% of control. In the state of fluid deficiency and elevated aldosterone concentration, there was a significant positive correlation between log excretion rate of HFT and excretion rate of sodium (r=0.68, P<0.002) calculated from excretion data 0–6, 6–12, and 12–14 hrs after the seventh dose. After the first dose of HFT, sodium excretion was also significantly correlated to log excretion rate of HFT (r=0.86, P<0.001) but was probably influenced by other factors as well. Mean serum concentration of uric acid increased significantly, but mean 24 hr-urinary excretion of uric acid was constant during HFT-treatment.     

Evidence of nonlinearity in digoxin pharmacokinetics

Six normal male volunteers received 0.5 mg label doses of digoxin as (a) a bolus intravenous injection over 2 min, (b) a constant rate intravenous infusion over 1 hr, (c) a constant rate intravenous infusion over 3 hr, and (d) a solution in 5% dextrose given orally. Plasma concentrations of digoxin were measured by radioimmunoassay for a 4 day period and urinary excretion for a 6 day period after the single doses. The mean (coefficient of variation) total areas under the plasma concentration-time curves per 0.5 mg of digoxin were (a) 35.55 (14.8%), (b) 30.20 (27.7%), (c) 25.80 (35.5%), and (d) 15.47 (49.9%); the means differed significantly (0.01>p>0.005). The mean (coefficient of variation) total amounts excreted in the urine as a fraction of the dose were (a) 0.689 (6.31%), (b) 0.517 (20.4%), (c) 0.588 (16.8%), and (d) 0.374 (23.4%); the means differed significantly (p<0.001. Both the total clearance and the nonrenal clearance of digoxin differed significantly with the method of intravenous administration. The slower the rate of input of digoxin to the body, the greater were both the total clearance and the nonrenal clearance of the drug, which strongly suggests nonlinear pharmacokinetics.This work was supported in part by National Institutes of Health Grant 1 R01 HL 23862-01 and in part by National Institutes of Health General Clinical Research Center Grant 5M01 RR421.     

Pharmacokinetics and bioavailability of intravenous and oral chlordesmethyldiazepam in humans

Summary Six healthy, fasting volunteers were given single doses of chlordesmethyldiazepam by 1 mg i. v., or as drops or tablets. Chlordesmethyldiazepam and its metabolite, lorazepam, in multiple plasma samples and in urine collected for 120 h after each dose were determined by electron-capture GLC.Mean kinetic variables for intravenous chlordesmethyldiazepam were: volume of distribution, 1.71 l · kg^–1; elimination half-life, 113 h; total clearance, 0.21 ml · min^–1 · kg^–1; cumulative excretion of lorazepam glucuronide 24.2% of the dose.Following a lag time of 15.5 min (tablets) and 4.2 min (drops), which were significantly different, the absorption of oral chlordesmethyldiazepam was a first order process, with apparent absorption half-life values averaging 1.5 h (tablets) and 1.1 h (drops). Bioavailability was 77% for tablets and 79% for drops.     

Pharmacokinetics of azidocillin in healthy adults

Two cross-over studies with azidocillin-sodium were carried out on healthy volunteers. In the first, we gave single doses of 375 mg, 750 mg, 1500 mg as tablets, 750 mg as a suspensions, i.m. and i.v. injections of 799 mg, and a course of 750 mg tablets twice daily for 14 days. In the second study, two 750 mg tablet batches were compared with the same dose i.v. Mean peak concentrations after 750 mg as tablets were 6.5-8 microgram/ml, as suspension 12.4 microgram/ml, and i.m. 18.5 microgram/ml. The urinary recovery of active antibiotic was 37-40% of the dose after the tablets, and nearly 50% after i.v. dosage. Thus, urinary elimination after the tablets was 75-83% of the amount eliminated after i.v. dosage. Bioavailabilities stipulated on the basis of the area under serum concentration curves in comparison with i.v. dosage were 57-60% for the tablets and 64% for the suspension. The bioavailability of the i.m. dose was comparable to that of the i.v. injection. The relatively small difference between the tablets and the suspension indicates that the tablets had favourable biopharmaceutical properties. Serum half-life of azidocillin was 0.6-0.7 h after the i.v. doses. For the other dosage forms, the half-life values varied between 0.6 and 1.1 h. The distribution volume Vd,beta ws 27-34 l after i.v. administration.