Quinidine pharmacokinetics in patients with cirrhosis or receiving propranolol.

Quinidine pharmacokinetics (half-life, volume of distribution, and clearance) as well as protein binding were evaluated following a single 200 mg. oral dose of quinidine sulfate in eight control patients, in eight patients with moderate to severe cirrhosis, and in seven patients receiving 40 to 400 mg./day of propranolol. Patients with cirrhosis had a significantly longer quinidine half-life (9 +/- 1 hr; p less than .01) when compared to control patients (6 +/- 0.5h). This was not related to a reduced quinidine clearance rate but rather to an increase in quinidine volume of distribution (4.1 +/- .4 L./Kg. in cirrhotic patients vs 2.6 +/- 1 L./Kg. in control patients; p less than .01). Abnormal quinidine binding (greater than 25 per cent unbound fraction) was noted in seven of the eight cirrhotic patients. In contrast, patients receiving propranolol had a normal quinidine half-life of 6 +/- 0.5 hr. However, these patients had a significantly reduced quinidine clearance (3.3 +/- .7 ml./min./Kg. vs. 5.3 +/- .5 ml./min./Kg. in controls; p less than .05) and higher peak concentrations (1.25 +/- .20 micrograms/ml. vs. .80 +/- .5 micrograms/ml. in controls; p less than .05). Therefore in patients receiving propranolol, quinidine levels may be higher than expected shortly after dosage, and therefore a potential for transient toxicity exists in these patients. Maintenance quinidine dosage may have to be reduced in patients with moderate to severe hepatic cirrhosis, but not in patients receiving propranolol. Total quinidine concentration measurement underestimate free quinidine concentrations in most cirrhotic patients.     

Intravenous quinidine: pharmacokinetic properties and effects on left ventricular performance in humans

Ten healthy volunteers received 300 mg. of quinidine base as the gluconate salt by 15-minute intravenous infusion. Physiologic variables monitored before, during, and for 24 hours after the infusion were: electrocardiogram, systolic and diastolic blood pressure, echocardiogram, and carotid pulse tracing. During quinidine infusion, mean ventricular rate increased by 18% (67.1 to 79.5 beats per minute) and corrected QT interval increased by 54% (0.44 to 0.68 sec.). QRS duration did not change significantly, nor did systolic or diastolic blood pressure. Ejection fraction (EF) measured by echocardiography did not decrease during quinidine infusion, but rather increased by 12% (0.58 to 0.65). Mean rate of circumferential fiber shortening (V_cf) likewise increased by 22%, from 1.15 to 1.40 per second. Over the 24-hours post-infusion, all monitored physiologic variables fluctuated considerably; in the case of EF and V_cf, apparently random variations over time were as great as those attributable to quinidine infusion. Mean (and range) kinetic variables for quinidine were: volume of distribution, 2.03 (1.47 to 3.00) liter/Kg.; elimination half-life, 6.3 (4.8 to 7.9) hours; total clearance, 3.8 (2.8 to 5.2) ml./min./Kg. Neither total nor unbound serum quinidine concentrations were significantly correlated with physiologic changes. Thus, intravenous quinidine in the doses studied did not have negative inotropic effects in a series of healthy humans.     

Pharmacokinetic evaluation of the digoxin-amiodarone interaction

Amiodarone is known to raise serum digoxin levels. This study was designed to evaluate the pharmacokinetic basis of this interaction in 10 normal subjects. The pharmacokinetic variables for digoxin were determined after a 1.0 mg intravenous dose of digoxin in each subject, before and after oral amiodarone, 400 mg daily for 3 weeks. During amiodarone administration, systemic clearance of digoxin was reduced from 234 +/- 72 ml/min (mean +/- standard deviation) to 172 +/- 33 ml/min (p less than 0.01). This was due to reductions in both renal clearance (from 105 +/- 39 to 84 +/- 15 ml/min) (p less than 0.05) and nonrenal clearance (from 130 +/- 38 to 88 +/- 20 ml/min) (p less than 0.01). Digoxin half-life of elimination was prolonged from 34 +/- 13 to 40 +/- 16 hours (p less than 0.05). Digoxin volume of distribution was not significantly changed. Amiodarone caused a three- to fivefold increase in serum reverse triiodothyronine levels, but changes in thyroid function were not quantitatively related to the changes in digoxin pharmacokinetics. These alterations in digoxin pharmacokinetics produced by amiodarone explain the increase in serum digoxin level that has been observed when this drug combination has been used clinically.     

Reduced quinidine clearance in elderly persons.

The influence of age on quinidine pharmacokinetics was assessed in 22 healthy male and female volunteers; 14 of the subjects were young (aged 23 to 34 years) and 8 elderly (aged 60 to 69 years). All subjects received 180 to 300 mg of quinidine base by constant rate intravenous infusion over 10 to 15 minutes. The concentration of total and unbound quinidine in multiple serum samples and in urine collected within 48 hours after the administration of quinidine qas determined with spectrophotofluorometric assay. Mean kinetic values for total quinidine in the young subjects were: elimination half-life (t 1/2 beta), 7.3 hours; total volume of distribution (Vd), 2.39 liters/kg; total clearance, 4.04 ml/min per kg; renal clearance 1.43 ml/min per kg; and percent unbound, 24.6 In the elderly subjects, the values for Vd (2.18 liters/kg) and percent unbound (28.2) did not differ significantly from these values in the young subjects. However, in the elderly subjects t 1/2 beta was significantly longer (9.7 hours, P less than 0.05) and total quinidine clearance significantly less (2.64 ml/min per kg, P less than 0.005) than in the young subjects. Renal clearance of quinidine in the elderly was also significantly less (0.99 ml/min per kg, P less than 0.05) than in the young and was associated with lower rates of creatinine clearance in the elderly (r = 0.66). Reduced clearance of quinidine and prolongation of its elimination half-life could predispose to toxicity in the elderly unless the dose were appropriately adjusted.     

Amiodarone-digoxin interaction: clinical significance, time course of development, potential pharmacokinetic mechanisms and therapeutic implications

Administration of amiodarone (600 to 1,600 mg/day) to 28 patients during long-term digoxin therapy (0.25 +/- 0.05 mg/day) increased serum digoxin level from 0.97 +/- 0.45 to 1.98 +/- 0.84 ng/ml (p less than 0.001). Gastrointestinal side effects occurred in nine patients, central nervous system reactions occurred in five and cardiovascular reactions occurred in four. Pharmacokinetic studies in six patients with a 1 mg intravenous digoxin dose before and during amiodarone therapy increased serum digoxin level at 30 minutes from 8.59 +/- 1.68 to 10.07 +/- 1.70 ng/ml (p less than 0.05). Amiodarone caused a 31% prolongation of digoxin elimination half-life from 49.5 +/- 8.8 to 65.0 +/- 28.8 hours, but the increase in half-life was not statistically significant. Total body clearance was reduced significantly (29%, p less than 0.05) from 2.05 +/- 0.76 to 1.46 +/- 0.64 ml/min per kg. Nonrenal clearance also showed a significant decrease (33%, p less than 0.05) from 1.20 +/- 0.46 to 0.80 +/- 0.30 ml/min per kg. The renal clearance decreased by 22% and the volume of distribution decreased by 11% after amiodarone therapy, but these changes were not significant. The data show that the mechanism of digoxin-amiodarone interaction is multifactorial and emphasize the need for close monitoring of serum digoxin levels and clinical features during concurrent digoxin-amiodarone therapy.     

Quinidine-digoxin interaction: Time course and pharmacokinetics

The time course of the rise in serum digoxin concentration was followed in 18 patients treated with digoxin as quinidine treatment was started with a loading dose. The mean serum digoxin levels rose significantly during the first 24 hours after administration of quinidine was begun, and reached a new steady state concentration after about 48 hours.

Digoxin kinetics were studied in two groups of normal volunteers: Group I (n = 7) received a small dose of quinidine, 800 mg/day, and group II (n = 8) received 1,600 mg/day. There was no significant mean change in the apparent volume of distribution of digoxin in either group. In group I (small dose), quinidine reduced the digoxin clearance values: total clearance by 30 percent, renal clearance by 32 percent and nonrenal clearance by 29 percent. In group II (large dose), quinidine reduced digoxin total clearance by 36 percent, renal clearance by 54 percent and nonrenal clearance by 22 percent. The reductions in digoxin volume of distribution and renal clearance during quinidine treatment were a function of the serum quinidine concentration. The change in nonrenal clearance of digoxin was independent of serum quinidine concentration.     

Study of serum digoxin status in digitoxicity by radioimmunoassay

Forty-seven patients who were being treated with digoxin in a daily dose range of 0.25 mg. to 0.75 mg. were the study material. Thirty-two patients were toxic. Seven patients out of these 32 were in an under-digitalized state and 15 patients were nontoxic. All patients were clinically assessed and investigated for routine hematological value, serum protein, electrolytes, serum creatinine, blood urea, and serum calcium.Serum digoxin concentration was estimated in all cases by the radioimmunoassay method. The assay was repeated after the patients recovered from toxic manifestations on withdrawal of the digoxin. The mean serum digoxin level in toxic patients (2.64 ± 0.68 ng./ml.) was significantly higher (P < 0.001) than that in nontoxic patients (1.35 ± 0.45 ng./ml.). After recovery from toxicity, the mean serum digoxin level (1.43 ± 0.32 ng./ml.) was found to be significantly lower than the level in the toxic patients and was similar to the level in patients of the nontoxic group. Seven patients whose symptoms simulated digitoxicity were in fact in an under-digitalized state (0.74 ± 0.35 ng./ml.), and their symptoms were relieved with a higher dosage of digoxin. In this study an attempt has been made to show the importance of the estimation of serum digoxin in the assessment of therapeutic and toxic effects of the drug so as to modify the dosage schedule for the optimal therapeutic response.     

Pharmacokinetics and safety of glimepiride at clinically effective doses in diabetic patients with renal impairment

Summary The pharmacokinetics, efficacy and safety of glimepiride were investigated in a single- and a multiple-dose open study in patients with non-insulin-dependent diabetes mellitus and renal impairment and an initial creatinine clearance above 10 ml/min. Patients were divided into three groups with creatinine clearance above 50 ml/min, 20–50 ml/min and under 20 ml/min. Fifteen fasting patients received a single dose of 3 mg glimepiride and serial blood and urine samples were taken over 24 h for pharmacokinetic and efficacy analyses. A further 16 patients received glimepiride over a 3-month period, an initial dose of 1 mg glimepiride being adjusted within the range 1 to 8 mg to achieve good glucose control. Pharmacokinetic evaluation was done on day 1 and after 3 months. Mean relative total clearance and mean volume of distribution of both single (41.6 ml/min and 8.47 litres, respectively, when creatinine clearance was above 50 ml/min) and multiple doses of glimepiride increased in proportion to the degree of renal impairment (to 91.1 ml/min and 14.98 litres, respectively, when creatinine clearance was below 20 ml/min, single dose), whereas the terminal half-life and mean time remained unchanged. Lower relative total clearance and renal clearance of both glimepiride metabolites correlated significantly with lower creatinine clearance values. Of the 16 patients 12 required between 1 and 4 mg glimepiride to stabilize their fasting blood glucose. Glimepiride was well-tolerated and there were no drug-related adverse events. In conclusion glimepiride is safe, effective and has clearly-definable pharmacokinetics in diabetic patients with renal impairment. The increased plasma elimination of glimepiride with decreasing kidney function is explainable on the basis of altered protein binding with an increase in unbound drug. [Diabetologia (1996) 39: 1617–1624]     

Digoxin disposition in obesity: Clinical pharmacokinetic investigation

Olgoxin pharmacokinetics were studied in 16 obese (mean ± SD weight, 100.2 ± 36.8 kg) and 13 control (64.6 ± 10.5 kg) subjects. all subjects had normal renal function and no other coexisting disease. After administration of 0.75 mg digoxin by intravenous intusion, multiple plasma samples obtained over the 96 hours following infusion were analyzed for digoxin concentration by radloimmunoassay. Pharmacokinetic parameters were determined by weighted iterative nonlinear least squares regression analysis. Elimination half-life ($\text{t}\text{1}\text{2}$) was not different between obese and control groups (35.6 ± 10.5 vs 41.2 ± 16.7 hours). Absolute volume of distribution (Vd) also was not different (981 ± 301 vs 937 ± 397 liters), nor was total clearance of digoxin (328 ± 82 vs 278 ± 87 ml/min). Elimination $\text{t}\text{1}\text{2}$ was significantly negatively correlated with clearance among all subjects (r = ?0.46; p < 0.01). Using percent ideal body weight (IBW) as a measure of obesity, no correlation was found between percent IBW and Vd (r = 0.03). Thus digoxin is simllarly distributed into IBW in obese and normal weight subjects, and there is no significant distribution of digoxin into excese body weight over IBW. In addition, there is no difference in total metabolic clearance or elimination half-life between obese and control subjects. Digoxin loading and maintenance dosage should be calculated on the basis of IBW, which reflects lean body mass, rather than TBW, which reflects adipose tissue weight in addition to lean body mass.     

Clinical pharmacology of mitoxantrone

A pharmacokinetic study on mitoxantrone was performed within the framework of a phase II clinical trial. Serum concentrations and urinary excretion were measured using a high-performance liquid chromatography method. Four metabolites were separated in urine and three in serum. The two major metabolites cochromatographed with the synthesized monocarboxylic and dicarboxylic acids of mitoxantrone. Within 48 hours, 4.4% of the administered dose was excreted in urine as mitoxantrone, 0.5% as Metabolite 1, and 0.3% as Metabolite 2. The pharmacokinetic parameters are adequately described by a three-compartment model with a terminal half-life of 214.8 hours and a volume of distribution of 2248 L/m2. The total-body clearance was 217 ml/min/m2 and the renal clearance was 15 ml/min/m2. These results suggest that mitoxantrone is sequestered in a deep tissue compartment and only slowly released.     

Absorption of Orally Administered Digoxin After Massive Resection of the Small Bowel

Digoxin absorption was studied in a patient after massive small bowel resection (with only 15 cm. of jejunum left) after mesenteric thrombosis. Oral administration of 0.25 mg. digoxin tablets resulted in therapeutic blood levels between 0.7 and 2.2 ng./ml. Measurement of the urinary excretion of the drug in steady state revealed more than 80% of the maintenance dose. Renal digoxin clearance was 125 ml./min. This resulted in slowing of the heart rate from 120 to 80/min. with no side-effects. It is thus concluded that total absorption of digoxin might be normal in a patient with only 15 cm. of jejunum and that usual dogs of digoxin were sufficient for a therapeutic effect and "therapeutic" blood levels     

Renal hemodynamics and pharmacokinetics of bevantolol in patients with impaired renal function

The effects of bevantolol on renal blood flow and glomerular filtration rate and the drug's pharmacokinetics were studied for 7 days in 18 patients (mean age 50 years) with varying degrees of renal dysfunction. Patients were divided into 3 groups: group 1 had a creatinine clearance of 50 to 80 ml/min, group 2, 20 to 49 ml/min and group 3, less than 20 ml/min. After baseline inulin and paraaminohippuric acid clearance values were obtained, patients were given a single, 150-mg "priming" administration of bevantolol. The kinetics of the drug (including plasma drug levels, plasma half-life and plasma clearance) and its effects on renal function were observed for 24 hours. On days 4 to 6 of the study, patients received 150 mg of bevantolol twice daily, with only a single dose given on day 7. Bevantolol did not significantly affect either inulin or paraaminohippuric acid clearance in patients with differing degrees of renal function. In 50% of patients with a creatinine clearance of less than or equal to 50 ml/min, both the half-life and maximum trough serum levels were higher than the ranges seen in healthy subjects. However, neither value appears to be clinically relevant because bevantolol has a wide therapeutic range. Renal impairment did not change the percentages of the bevantolol dosage excreted unchanged or as conjugated drug in the urine, and no toxic or active drug metabolites accumulated in the blood. From these results, it appears that bevantolol may be used safely in short-term therapy of patients with renal impairment.     

Advancing age and acute infection influence the kinetics of ceftazidime

The pharmacokinetics of ceftazidime were studied after single intravenous injections of 2 g in 10 healthy, elderly male volunteers (63-76 years old). None of the subjects were on concurrent drug treatment and all had normal age-correlated glomerular filtration rate. Mean values for major pharmacokinetic variables were: terminal half-life 2.63 h, area under the serum concentration curve 417.6 h mg/l, total clearance 74.6 ml/(min 1.73 m2), renal clearance 53.6 ml/(min 1.73 m2), urinary recovery/12 h 71.7% of dose and apparent volume of distribution (Vss) 15.0 l/1.73 m2. Data were compared with our earlier findings in studies of young male volunteers and elderly, acutely ill male patients. Advanced age was accompanied by a reduction in clearance of ceftazidime, while no significant age-related changes in distribution were noted. Acute infection was associated with increased Vss and enhanced renal clearance; alterations possibly caused by fever-induced changes in vascular permeability and renal blood-flow.     

The effects of exercise training on the pharmacokinetics of digoxin

BACKGROUND: Studies have shown that digoxin binds to the working muscles during an acute bout of exercise, with a concomitant decrease in serum digoxin concentration. This study investigated the effects of 16 weeks of endurance exercise training on the pharmacokinetics of digoxin in old and young adults. METHODS: Twelve subjects, aged 68.5 +/- 4.5 years, and six subjects, aged 30.3 +/- 3.8 years, completed the study. All subjects were healthy, sedentary, and taking no cardiovascular medications. After initial testing and maximum oxygen consumption (VO2max) measurements, subjects were hospitalized for 28 hours for renal function testing and digoxin clearance studies and then randomly assigned to an exercise (EG) or control (CG) group. The EG completed 16 weeks (three 1-hour bouts/week) of aerobic training at 75% to 85% of maximum capacity. The CG did not exercise. All tests were repeated at the end of the 16-week study period. RESULTS: In the older EG subjects, VO2max increased by 3.4 ml/kg/min, or approximately 16% (P = 0.0002). VO2max increased in the younger EG subjects by 1.1 ml/kg/min, but the increase was not significant (P > 0.05). There were no significant changes in body composition, renal function, or time of onset, peak concentration, or elimination phase half-life of digoxin in either the old or young exercise or control groups (P > 0.05 for all variables). CONCLUSION: Although 16 weeks of endurance exercise training improves cardiorespiratory fitness, the pharmacokinetics of digoxin are neither improved nor adversely affected in healthy old and young adults.     

Pharmacokinetics of sisomicin in normal patients and those with depressed renal function

The pharmacokinetics of sisomicin were studied in 29 patients and seven patients on chronic hemodialysis. The mean peak serum levels after intramuscular injection were 3.55 µg/ml at 0.5 hours. Levels of 1.5 µg/ml were present at six hours. The mean half-life of the drug varied with the renal function. In normal individuals the half-life is 1.85 hours. The apparent volume of distribution is 17.9 liters. 81% of a dose is recovered in the urine in a 12 hour period. Sisomicin is removed by hemodialysis with an average half-life of six hours and 39% removed during a six-hour dialysis period.     

Administration of human recombinant insulin-like growth factor-I to patients following major gastrointestinal surgery

OBJECTIVE: The aim was to study the pharmacokinetic parameters and biological activity of a single dose of human recombinant IGF-I (rhIGF-I) administered to patients following major gastrointestinal surgery. DESIGN: A double blind placebo controlled externally randomized study of 30 patients; the study commencing 24 hours after major colonic or gastric surgery. MEASUREMENTS: After a baseline blood sampling day, IGF-I (40 micrograms/kg by single subcutaneous dose, n = 20) or placebo (n = 10) was administered and serum and urine samples collected over the ensuing 72 hours. Serum IGF-I, IGF-II, IGF binding proteins (IGFBP-1, IGFBP-3), GH and insulin were measured by radioimmunoassay. Serum IGF bioactivity was assessed using a validated porcine cartilage bioassay. Serum and urinary electrolytes were measured by standard methodology. RESULTS: Serum immunoreactive IGF-I levels peaked at 4 hours following injection of IGF-I (1.09 +/- 0.12 U/ml mean +/- SEM), remained elevated for 15 hours and returned to basal levels by 24 hours after injection. IGF bioactivity was increased by 57% 6 hours after IGF-I injection. Mean levels of IGFBP-1 and IGFBP-3, IGF-II and GH were unaffected by IGF-I administration. Insulin levels were suppressed at 30 minutes following injection of IGF-I compared with the placebo group (16.9 +/- 3.0 mU/I vs 32.3 +/- 7.1, P = 0.02); thereafter, there were no differences in insulin levels. The mean change in serum creatinine following IGF-I (-6.3 +/- 3.0 mmol/l) was significantly different from that in the control group (+7.2 +/- 6.2, P = 0.03). Creatinine clearance rose from a mean of 71.6 +/- 7.5 ml/min to 83.2 +/- 7.6 ml/min after IGF-I treatment (P = 0.02). In the IGF treated patients, cholesterol levels consistently fell (-0.20 +/- 0.05 mmol/l); this was not observed in the placebo group (+0.20 +/- 0.14, P = 0.006). Basal serum potassium levels in the IGF treatment group (4.1 +/- 0.1 mmol/l) fell to 3.8 +/- 0.1 at 4 hours (P = 0.002) and 3.6 +/- 0.1 at 10 hours (P = 0.001) returning to a level of 4.0 +/- 0.1 (P = 0.293) at 24 hours after injection. There were no other observed differences in serum or urinary electrolytes or serum free fatty acids and triglycerides. Pharmacokinetic parameters derived from baseline adjusted IGF-I measurements revealed a slow absorption of the administered dose with a Tmax of 5.0 +/- 0.43 hours and an elimination half-life of 10.8 +/- 1.2 hours. The computed volume of distribution was 0.33 +/- 0.05 I/kg and the clearance on average 25 ml/min. CONCLUSION: A single subcutaneous dose of IGF-I normalized circulating IGF-I levels in post-operative patients, was well tolerated and without side-effects. IGF bioactivity was increased and associated with a fall in serum cholesterol, potassium and creatinine levels and a rise in creatinine clearance. Further long-term studies are now required to assess the anabolic effects of rhIGF-I in this type of patient group.     

Pharmacokinetics of bleomycin after im administration in man

The pharmacokinetics of bleomycin were studied after im injection in patients with malignant lymphoma. Mean peak serum concentrations of 0.133, 0.326, and 0.587 milliunits/ml were obtained approximately 1 hour after injection of 2, 5, and 10 units/m2, respectively. The mean half-life was 155 minutes, with a range of 65--235 minutes. Thirty-three percent of the administered dose was recovered in the urine after 4 hours. The urinary excretion of bleomycin was 61% during the 24 hours after injection, with some variability that was not explained by differences in dose or creatinine clearance.     

Effect of propafenone on the pharmacokinetics of digoxin administered orally: a study in healthy volunteers

It is well known that many cardiovascular drugs affect digoxin kinetics, but nothing is defined on propafenone-digoxin interaction. To clarify this problem, we studied digoxin kinetics in 8 healthy men, who received digoxin oral dose (0.50 mg) in the control state and again during maintenance therapy with propafenone (150 mg q.i.d.). Statistically significant changes were observed during propafenone in a number of digoxin kinetic indexes: a rise in peak serum digoxin concentration (4.30 vs 3.07 ng/ml - p less than 0.005), in area under the serum-digoxin concentration curve (4 h: 520.4 vs 368.9; 10 h: 789.6 vs 621.3 ng X min/ml - p less than 0.005; 24 h: 1187.6 vs 954.7 ng X min/ml - p less than 0.05) and urinary excretion of digoxin (277.7 vs 203.5 mcg - p less than 0.005). Renal digoxin clearance was not affected by propafenone. We conclude that propafenone interact kinetically with digoxin in healthy subjects, perhaps increasing digoxin bioavailability.     

Ethambutol kinetics in patients with impaired renal function

The pharmacokinetics of ethambutol (EMB) were investigated in 13 hospitalized patients with varying degrees of compromised renal function. Each patient was administered 15 mg/kg EMB by a constant-rate, 1-h infusion. Plasma and urine samples were collected for as long as 24 and 96 h, respectively, for analysis of EMB by electron capture gas-liquid chromatography. Plasma EMB concentrations appeared to decline multi-exponentially, with a terminal phase half-life of 7.4 to 11.8 h. Total body clearance of EMB ranged from 2.0 to 9.6 ml/min/kg and the steady-state volume of distribution from 0.80 to 3.60 L/kg. The fraction of EMB dose excreted unchanged in the urine varied from 0.03 to 0.26, and renal clearance varied from 0.07 to 0.57 ml/min/kg. The results of this study clearly indicate that renal failure decreases total body clearance and renal clearance and prolongs elimination half-life of EMB when compared with that in normal volunteers. The terminal phase elimination rate constant correlated significantly with creatinine clearance and the reciprocal of serum creatinine (y = 0.037 X +0.060, r = 0.795, p less than 0.05; y = 0.042 X +0.061, r = 0.783, p less than 0.05, respectively). Either creatinine clearance or serum creatinine of an individual patient would thus serve as a useful predictor for his or her capacity to eliminate EMB. Dosage adjustment is mandatory for EMB in patients with compromised renal function in order to achieve optimal therapy and to avoid undesirable side effects.     

Pharmacokinetics and bioavailability of digoxin capsules,solution and tablets after single and multiple doses

The bioavailability of single doses of digoxin capsules (0.4 mg), digoxin solution (0.4 mg) and reference tablets (0.5 mg) was compared with that of single intravenous doses (0.4 mg) of digoxin using measurement of 24 hour urinary excretion and area under the plasma concentration curve. The absolute systemic availability of all three oral preparations was significantly less than 100 percent. The bioavailability of capsules and solution was nearly identical (79 percent and 76 percent, respectively, as assessed with values for area under the concentration curve and 65 percent and 62 percent as assessed with urinary excretion values); both forms had greater systemic availability than the tablet, which had bioavailability values of 50 percent using area under the curve and 41 percent using urinary excretion. Capsules and solution also were similar in peak plasma digoxin levels achieved (3.7 and 3.1 ng/ml), time of peak concentration (0.8 and 0.6 hour after dosage) and apparent first order absorption half-life (11.3 and 10.2 minutes); both capsules and solution differed significantly from tablets (peak level 1.6 ng/ml, time of peak concentration 1.2 hours and absorption half-life 27.1 minutes). Single dose findings were substantiated when steady state plasma levels and 24 hour urinary excretion values were measured from days 11 through 16 of the period of once daily ingestion. Mean plasma levels (0.70 ng/ml) and urinary excretion values (45.1 percent of dose) for capsules were nearly identical to those for solution (0.69 ng/ml and 42.5 percent of the dose), and values for both capsules and solution were significantly greater than those for tablets. Within- and between-subject variation in bioavailability was similar for the three oral preparations. Thus the single dose bioavailability study was predictive of the steady state findings. The bioavailability of digoxin capsules is equivalent to that of a solution and significantly greater than that of a reference tablet formulation.