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.     

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     

Digoxin prescribing in perspective

1 Prescribing aids based on creatinine clearance were evaluated in 86 out-patients taking digoxin at a district general hospital. Lanoxin tablets were dispensed in calendar packs to encourage patient compliance.

2 Despite a high degree of patient compliance and a more than three-fold variation in creatinine clearance the range of concentrations that would result from prescribing individual doses based on creatinine clearance was similar to that expected from prescribing one fixed dose for all male and another for all female patients.

3 Concentrations at which symptoms of toxicity occurred in 31 patients did not differ significantly from concentrations achieved in the remainder.

4 Only 17% of the variance in resting ventricular rate in patients with atrial fibrillation and no serious impairment of atrio-ventricular conduction was explained by the serum digoxin concentration.

5 Even when the serum digoxin concentration is known the patient's clinical condition must be the final determinant of dose.

6 Patients with symptoms of toxicity were distinguished by significantly lower serum creatinine concentrations and body weights, factors suggestive of a lower muscle mass. No other biochemical or clinical (other than serum digoxin concentration) factors influencing resting ventricular rate in atrial fibrillation were identified.

     

Assessment of bio(in)equivalence of deriphyllin-digoxin in human volunteers. II. Evaluation of rabbits as qualitative animal model

In rabbits, a three way cross-over test was carried out to assess bioavailability of digoxin from commercially available 'Deriphyllin-Digoxin' tablets. The in vitro dissolution test showed that these tablets had low dissolution even at the end of 4 hr. The in vivo tests in rabbits compared bioavailability of digoxin from Deriphyllin-Digoxin tablets with that from Lanoxin tablets and intravenous digoxin injection. The treatments were given in randomized order with a minimum of 14 days wash-out period between the treatments. After the drug administrations, periodic blood samples were collected and plasma digoxin concentrations were analysed using radioimmunoassay. As indicated by the results of in vitro dissolution tests, Deriphyllin-Digoxin tablets showed poor and delayed absorption of digoxin in vivo. A parallel study on comparative bioavailability for the same batches of digoxin tablets was also carried out in human volunteers. The study in human volunteers involved 14 subjects and had a cross-over dosing. The bioavailability results in rabbits were qualitatively similar to human bioquivalence studies. This is the first report showing digoxin bioavailability in rabbits corresponding to that in humans. The importance of the rabbit as a secondary model for bioequivalence testing of digoxin formulations has been emphasized.     

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.     

Bioavailability studies with Digoxin-Sandoz® and Lanoxin®

Summary Various brands of digoxin tablets, and even different batches of one brand, may differ greatly in bioavailability. Digoxin-Sandoz^® tablets have been compared with Lanoxin^® manufactured between 1969 and 1972 and after May 1972. Comparisons were also made between and within batches of Digoxin-Sandoz tablets. Three separate cross-over studies were conducted involving a total of 20 volunteers. Digoxin-Sandoz tablets were shown to have a constant bioavailability and to produce plasma concentrations very similar to new Lanoxin. Storage for 2 years of one batch of Digoxin-Sandoz did not alter the bioavailability. Particle size was shown to influence bioavailability. Care should be exercised when plasma data alone are interpreted as an index of bioavailability. Measures of bioavailability based on plasma data obtained up to 6 h after administration differed from those based on cumulative urinary excretion data (in this study by a factor of about 2), which can lead to the belief that a difference in bioavailability is much greater than is actually the case. Data from cumulative urinary excretion, collected over a sufficiently long period of time, are likely to be the most reliable method for determining the bioavailability of a substance such as digoxin.     

Influence of soft gelatin on digoxin absorption.

1 The influence of encapsulation in soft gelatin on the absorption of digoxin from a solvent mixture of polyethylene glycol 400 90% W/W, ethanol 6% W/W, propylene glycol 3% W/W and water 1% W/W was studied in eight healthy volunteers. 2 Each volunteer received 0.6 mg digoxin as solution alone, as three intact capsules containing digoxin solution, as three capsules containing digoxin solution sectioned in half and as three capsules containing digoxin solution dissolved in water prior to administration. 3 There was no significant difference between the four treatments in terms of area under the plasma concentration--time curves for 7 h, peak plasma concentrations, time to peak or in the cumulative urinary excretion for 6 days. 4 It is suggested that a constituent of the solvent rather than the presence of or encapsulation within soft gelatin may be the determining factor in enhanced absorption of digoxin from soft gelatin capsules as compared to aqueous solution or tablets of rapid dissolution rate.     

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.     

Effect of urinary pH and nicotine excretion rate on plasma nicotine during cigarette smoking and chewing nicotine gum

1 Plasma nicotine levels produced by chewing nicotine gum were compared with those obtained by cigarette smoking under conditions of controlled urinary pH.

2 Although absorption was slower, plasma levels comparable to cigarette smoking were built up on 4 mg (but not 2 mg) nicotine gum.

3 Urinary excretion of nicotine was influenced markedly by pH and the rate of urine flow.

4 Plasma nicotine was higher under alkaline compared to acidic conditions (P < 0.001) but the rate of urinary nicotine excretion appeared to have little effect on the plasma level.

     

Urinary D-glucaric acid excretion and plasma antipyrine kinetics during enzyme induction

1 Changes in urinary D-glucaric acid excretion following a 14 day course of antipyrine to produce enzyme induction have been compared in normal volunteers with changes in plasma half lives and steady state levels of antipyrine.

2 Urinary D-glucaric acid excretion for the group rose significantly with induction, while there was a significant fall in the mean plasma antipyrine half life and steady state levels. The extent of the increase in urinary D-glucaric acid excretion was inversely related to the pre-induction level, and this also applied to the change in antipyrine half lives.

3 Although in individuals, urinary D-glucaric acid excretion and plasma levels of antipyrine changed in parallel, there was no numerical correlation in the group as a whole between these two tests either before or after enzyme induction.

4 These findings are consistent with other recently reported evidence that plasma drug kinetics and other microsomal enzyme functions are not necessarily affected to the same degree by agents with enzyme inducing properties.

     

Absorption of digoxin from a new microencapsulated formulation

Summary The absorption of digoxin from two capsule preparations containing a large number of small, enteric-coated granules of the glycoside (0.38 mg) was compared with that of the same amount from ultrarapidly dissolving commercial tablets. Eight volunteers were studied during steady state conditions. Digoxin concentrations in plasma and urine were measured by radioimmunoassay. Peak plasma concentrations of digoxin were significantly (p<0.01) delayed after taking the capsules (2.6±1 h and 2.6±0.9 h, mean±SD) as compared to the tablets (1.3±0.7 h). The peak concentrations produced by the capsules were 3.1±1.0 and 2.6±1.1 nmol/l; only the latter was significantly (p<0.05) lower than after the tablets (3.4±1.0 nmol/l). Areas under the plasma concentration-time curves during a 24 h dosage interval were similar for the three preparations, and so was the 24 h urinary excretion of digoxin, which averaged 60–63% of the daily dose. Thus, this particular enteric coating of digoxin delayed absorption without reducing the amount absorbed.     

The influence of compression and formulation on the hardness, disintegration, dissolution, absorption and excretion of sulphadimidine tablets

Sulphadimidine tablets were prepared with different binding agents and compressed at different compression levels, ranging from 200–2000 MNm². The disintegration time and dissolution rate of the different tablets were determined. Tablets formulated with gelatin or starch mucilage and compressed at 600 MNm² were selected for in vivo experiments using a urinary excretion method. Although both tablets complied with the disintegration requirements of the British Pharmacopoeia, dissolution rate and urinary excretion showed a difference in availability of drug from the two tablets.     

Metformin kinetics in healthy subjects and in patients with diabetes mellitus

1 The kinetics of metformin were studied after i.v. and oral administration in four healthy subjects and after oral administration in twelve maturity onset (Type II) diabetic patients.

2 After i.v. administration most of the dose was rapidly eliminated but with a mean `terminal' T_1/2 of 4 h measured up to 12 h in plasma and of 16 h measured up to 60 h from the urinary excretion rate. On average, 80% of the dose was recovered as unchanged drug in the urine with none detected in the faeces.

3 After single oral doses (0.5 and 1.5 g), maximum plasma concentrations and urinary excretion rates were observed at about 2 h with urinary recoveries of unchanged drug of 35-50% and faecal recoveries of about 30%. Urinary recoveries were significantly lower after the higher dose. Absolute oral bioavailability was 50-60% of the dose.

4 Deconvolution analysis showed that after a short lag-time, the available oral dose was absorbed at an exponential rate over about 6 h. Implications for the design of prolonged release dosage forms are discussed.

5 Plasma metformin concentrations measured throughout the seventh and fourteenth days of continuous 0.5 g twice daily treatment were accurately predicted from single dose data, although a discrepancy between observed and predicted trough levels reflected the existence of a slow elimination phase. Implications of the latter for a gradual accumulation of metformin in peripheral tissues and a possible association with lactic acidosis are discussed.

6 Renal clearance of metformin was highly correlated with creatinine clearance. However, a weaker relationship between total oral clearance of the drug and creatinine clearance suggests that the latter may not always be a reliable indicator of potential metformin accumulation owing to variability in absorption and possibly non-renal clearance of the drug,

     

Availability of methaqualone from commercial preparations: in vitro and in vivo studies in man

1 The plasma profiles of methaqualone obtained from different commercially available preparations have been compared. Tablets were absorbed more efficiently than capsules. Mandrax preparations achieved much higher plasma levels than Melsedin tablets or the Melsed or Sedaquin capsules. These differences appear to be due to formulation factors.

2 The efficacy of the different drugs as hypnotics corresponded well with the blood levels achieved.

3 There was a significant correlation between the in vitro l/t_50% and the in vivo peak plasma levels. Thus in vitro dissolution studies can be used to predict the efficiency of absorption of different formulations in man.

     

The disposition of debrisoquine in hypertensive patients

1 The urinary recovery and plasma concentration of debrisoquine (D) and its metabolite 4-hydroxydebrisoquine (HD) has been studied following single and multiple oral administration of debrisoquine hemisulphate to 15 hypertensive in-patients and four normal volunteers.

2 Incremental doses and prolonged administration led to a proportionately greater urinary recovery and higher plasma concentration of D but the proportion recovered as HD fell while its plasma concentration remained unchanged. Dividing a dose or administering a single oral dose of D resulted in the formation of proportionately more HD and a lower urinary recovery of D. These findings suggest that the metabolism of D to HD may be partially saturated or inhibited by D itself or by HD.

3 Peak urinary excretion rates and plasma concentrations of both D and HD occurred 2 h after a single dose suggesting rapid absorption and presystemic metabolism.

4 HD was eliminated more rapidly than D. Mean (± s.d.) elimination half-life from the urine for HD was 9.6 ± 3.7 h and for D was 16.2 ± 5.7 h. Reasons for this are discussed.

5 Renal clearance of D and HD was not constant. A fall was observed with time after a single dose but on multiple dosing the clearance fell with increasing plasma concentrations. Mean (± s.d.) renal clearance values during multiple administration were D 282 ± 88 ml/min and HD 371 ± 178 ml/min. It is suggested that active saturable tubular secretion of D and HD may be responsible for their renal elimination.

6 The distribution of D in the blood was studied after a single dose to one volunteer. The greatest concentration of the drug was in the platelet rich fraction from which it was eliminated slowly. The elimination half-lives in plasma and platelet rich plasma were 17.5 h and 56 h respectively.

7 On early multiple dosing the hypotensive response was related to high plasma D concentrations.

     

Plasma dopa concentrations after different preparations of levodopa in normal subjects

1 The concurrent administration of levodopa with a decarboxylase inhibitor produced a plasma concentration/time curve comparable with 1/4 to 1/5 of the dose of levodopa given alone.

2 There was no evidence to suggest that the decarboxylase inhibitor slowed the rate of elimination of levodopa from plasma.

3 Metoclopramide (Maxolon) increased the rate of levodopa absorption. Higher plasma concentrations of levodopa during the first 2 h after dosing were followed by lower plasma concentrations during the third and fourth hours. The amount of levodopa absorbed after Larodopa as indicated by the AUC was not altered by adding metoclopramide.

4 None of the current preparations of levodopa produced sustained plasma concentrations.

5 In vitro testing confirmed that Brocadopa Temtabs tablets disintegrate and dissolve slowly. In vivo, Brocadopa Temtabs behaved as a slow release preparation but it did not produce sustained plasma concentrations of levodopa.

     

A comparison of the effect of frusemide and bumetanide on the diuretic response and fibrinolytic mechanism in man

1 A double-blind, crossover trial has compared the diuretic response of ten normal male subjects to the oral administration of frusemide (40 mg) and bumetanide (1 mg).

2 Both drugs gave a similar profile, with acute onset and cessation of response, and a marked peak effect.

3 There was no significant difference between the times taken for each drug to produce its peak diuretic effect.

4 The peak rate of diuretic response, and the total response for six hours after drug ingestion, were significantly greater after bumetanide, with respect to urinary volume and sodium excretion. The peak rate of magnesium excretion was greater after bumetanide. There was no difference between the drugs with respect to potassium, calcium or creatinine excretion or the urinary Na/K ratio. Following peak diuresis, potassium excretion did not show a linear return to its control value.

5 At the time of peak diuresis, both drugs caused a significant reduction of euglobulin lysis time; levels of available plasmin were significantly lowered after frusemide, and levels of active plasmin were significantly raised after bumetanide. The significance of these findings in relation to the fibrinolytic mechanism is discussed.

6 Estimations of plasma viscosity, serum total protein and magnesium concentrations showed that maximal haemoconcentration occurred several hours after diuresis.

     

Effect of caroxazone, a new antidepressant drug, on monoamine oxidases in healthy volunteers

1 Caroxazone is a new antidepressant drug with a reversible inhibitory effect on monoamine oxidases (MAO) as previously shown experimentally in animals.

2 The effect of caroxazone on MAO was explored in healthy volunteers and compared with that of tranylcypromine and imipramine. Daily urinary excretion of tryptamine and MAO activity in platelets were assayed at various times during and after treatment and the differences from basal values were statistically analysed. In addition, caroxazone plasma levels were determined.

3 Caroxazone administered orally at doses of 300 or 600 mg/day for 12 days induced a significant, dose-dependent increase in urinary tryptamine excretion. Tranylcypromine (20 mg/day for 8 days) was even more active in this respect; imipramine (50 mg/day for 12 days) was completely inactive.

4 MAO activity in platelets was not affected by caroxazone or imipramine, but was completely inhibited by tranylcypromine.

5 Mean steady-state plasma levels of caroxazone were about 6 μg/ml and 11-12 μg/ml with the dose of 300 mg/day and 600 mg/day respectively.

6 It can be concluded that caroxazone is a MAO inhibitor in man too, at a clinically effective dose such as 600 mg/day. The fact that its MAO inhibition is not apparent in platelet preparation may be explained by its reversibility.

7 Tranylcypromine confirmed its potent irreversible MAO inhibitory effect, while imipramine lacked any effect at the tested dose.

     

The influence of diphenhydramine on the absorption of methaqualone in man

1 The effects of diphenhydramine on the buccal absorption, in vivo absorption and the in vitro dissolution of methaqualone have been studied.

2 Diphenhydramine significantly reduced the buccal absorption of methaqualone and the effect was dose and pH dependent. In vivo, diphenhydramine did not alter the rate of absorption or the distribution of methaqualone in blood. In vitro, the presence of diphenhydramine increased the rate of dissolution of methaqualone and the effect was more marked when the particle size was small.

3 The reasons for and the implications of these apparently contradictory results are discussed and it is concluded that any increased efficacy resulting from combining diphenhydramine with methaqualone cannot be due to increased plasma drug levels.

     

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%.