Clinical study on digoxin tablets with high bioavailability (author's transl)

The relationship between different maintenance doses and the steady-state digoxin blood concentration was studied in 160 patients with heart failure. All patients received digoxin tablets of the same brand (Digacin). The bioavailability of this brand is 82% compared with an i.v. standard. During the treatment with daily doses of 0.2 mg and 0.3 mg average serum digoxin levels of 1.09 +/- 0.45 ng/ml and 1.33 +/- 0.53 ng/ml were measured in patients with normal renal function. The daily dose of 0.4 mg digoxin was in correlation to an average serum level of 1.75 +/- 0.81 ng/ml. 81% and 86% of all patients with normal renal function taking 0.2 or 0.3 mg digoxin every day were found to have levels in the range of 0.7 to 2.0 ng/ml. The influence of sex, age, height, body weight, maintenance dose, serum creatinine and serum potassium on the variance of the digoxin plasma levels was computed by multiple linear regression. The multiple correlation coefficient was r = 0.666, the coefficient of determination (100 r2) being 44.4%. Therefore 44.4% of the total variance could be explained by these variables. Individual variables accounted for the following percentages of the total variance: serum creatinine 29.1%; maintenance dose 14.5%; age 4.3%; and reciprocal of body weight 3.9%.     

Dose requirement and prolactin elevation of antipsychotics in male and female patients with schizophrenia or related psychoses

AIMS: The aim of this study was to investigate the prolactin (PRL) secretion and the growth hormone (GH)-insulin-like growth factor I (IGF-I) axis in relation to gender and side-effects and dose of antipsychotic drugs during long-term treatment. METHODS: Forty-seven patients (21 men and 26 women), diagnosed with schizophrenia or related psychoses according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria and treated with different classical antipsychotics, were studied. Prolactin, GH and IGF-I were measured, as well as the serum concentration of the antipsychotics. In addition, body mass index (BMI) was calculated. RESULTS: The median daily, as well as the median body weight, adjusted daily dose of antipsychotic drugs was twofold higher in male compared with female patients. Antipsychotic-induced hyperprolactinaemia was more frequent and occurred at a lower daily dose of antipsychotics in women. Irrespective of sex, more than half of the patients had elevated BMI. Two patients had a slight increment in IGF-I levels, whereas the GH concentration, as assessed on a single occasion, was normal in all patients. CONCLUSIONS: Patients on long-term antipsychotic therapy, with doses adjusted according to therapeutic efficiency, exhibited hyperprolactinaemia and elevated BMI, but no obvious influence on the GH-IGF-I axis. Furthermore, it appeared that the males required twice the dose of antipsychotic compared with females.     

Effects of gender and race on albuterol pharmacokinetics

We evaluated the effects of race and gender on albuterol pharmacokinetics in 30 patients with moderate asthma (15 blacks, 15 whites, 16 men, 14 women). Subjects received a single dose of albuterol 8 mg oral solution and had blood samples collected at various times for 12 hours after the dose. Albuterol plasma concentrations were determined by HPLC with fluorescence detection, and pharmacokinetics were determined by compartmental analysis. The apparent volume of distribution of albuterol was significantly higher in men than in women (631+/-171 and 510+/-109 L, respectively, p<0.05). Consequently, the maximum concentration was lower in men than women (10.3+/-2.1 and 12.0+/-1.9 ng/ml, respectively, p<0.05). Elimination rates were 0.136+/-0.008 and 0.160+0.012 hour(-1), respectively (p<0.10). When corrected for ideal body weight, apparent volume of distribution was not different by gender. No differences between blacks and whites other than lag time were noted in albuterol kinetics. The greater apparent volume of distribution in men is likely explained by differences in ideal body weight or lean body mass.     

Development of dosing guidelines for reaching selected target breath alcohol concentrations.

OBJECTIVE: This study evaluated gender-specific ethanol dosing protocols that were designed to result in one of two peak breath alcohol concentrations (BrACs)--0.07 or 0.10 g/2101. Inter- and intrasubject variability in BrAC were assessed and several possible methods for reducing variability in BrAC were evaluated. METHOD: Subjects (16 women, 16 men, ages 21-30 years) were studied after low (women 0.49 g/kg, men 0.53 g/kg consumed over 10 minutes) and high (women 0.81 g/kg, men 0.89 g/kg consumed over 20 minutes) ethanol doses, consumed following a 4-hour fast. All subjects were regular drinkers. RESULTS: Mean (+/-SD) peak BrACs actually achieved were 0.069+/-0.011 g/2101 after the low dose, and 0.105+/-0.014 g/2101 after the high dose. Mean values for peak BrAC, time to peak BrAC and area under the curve were not statistically significantly different between genders at either dose. BrACs varied by as much as twofold between subjects after equivalent gender and body weight adjusted doses. There was some reproducibility of ethanol pharmacokinetic parameters over dose and time in men, but not in women. CONCLUSIONS: The doses used resulted in equivalent mean ethanol exposures for women and men at each dose, with mean peak BrACs that closely approached the targets, but there was substantial inter- and intrasubject variability in ethanol pharmacokinetics.     

Effect of renal function on the pharmacokinetics of enoxaparin and consequences on dose adjustment

The use of weight-adjusted enoxaparin dosage in patients with renal failure results in increased bleeding complications. The authors investigated the impact of patient-related factors such as renal function on the pharmacokinetics of enoxaparin. Anti-Xa activity was measured in the blood of 60 patients (74 +/- 10 years, body weight 72 +/- 15 kg, men 60%, creatinine clearance 56 +/- 24 mL/min) with acute coronary syndromes receiving subcutaneous administration of enoxaparin. A population-based approach with limited sampling strategy was used. A 1-compartment model with first-order absorption and elimination best fitted the data. The mean clearance (CL/F) and distribution volume (V/F) were 0.72 L/h and 6.65 L, respectively. V/F was influenced by body weight. CL/F was mainly related to the renal function, decreasing with increasing levels of serum creatinine, and lower in women than in men. The elimination half-life was thus estimated to be 6.4 and 9.2 hours in male and female patients, respectively. The final covariate submodel was then: [Equation included in full-text article]. Maximal anti-Xa activity was predicted to rise above 1.5 IU/mL in case of mild elevation of serum creatinine according to gender and body weight. Renal function is the main factor affecting enoxaparin pharmacokinetics. In patients with decreased renal function, enoxaparin dose should be adjusted on the basis of body weight, serum creatinine, and gender to reach a target anticoagulation level assessed by maximal anti-Xa activity in steady-state conditions.     

Gatifloxacin pharmacokinetics in healthy men and women

The sex-based pharmacokinetics of gatifloxacin were investigated. Healthy subjects (6 men, 6 women) received a single oral dose of gatifloxacin 400 mg. Blood and urine samples were collected, and gatifloxacin concentrations were determined by high-performance liquid chromatography. Pharmacokinetic parameters were estimated by fitting appropriate models to the serum concentration-time data using ADAPT II. Linear regression analysis was used to determine the influence of sex and weight on the oral clearance (CL(s)/F) and apparent steady-state volume of distribution (V(ss)/F) of gatifloxacin. Women had a significantly smaller V(ss)/F compared to men (93.5 +/- 21.3 L vs 128.8 +/- 16.2 L, P = .009); however, there was no significant difference when normalized for total body weight (TBW) or lean body weight (LBW). Neither CL(s)/F nor peak serum concentration (C(max)) was significantly different between sexes, although C(max) was 25% higher in women (P = .06). Regression analyses revealed that TBW (R(2) = .63) and LBW (R(2) = .65) were strong predictors of V(ss)/F. Given the smaller V(ss)/F, women may have slightly higher maximum concentrations, but these differences are unlikely to have clinical significance.     

Serum digoxin concentrations in a representative digoxin — Consuming adult population

Summary As part of health examination of a representative sample of an adult population (n=8000) serum digoxin concentration was measured in 661 patients on continuous digoxin therapy. The prescribed mean daily dose of digoxin was significantly higher in men (223 µg) than in women (201 µg); the dose significantly decreased with increasing age. The mean serum digoxin concentration was the same in men and women and it differed insignificantly between age groups, although older persons tended to have a higher concentration. The age — adjusted mean steady state digoxin concentration was 1.02 ng/ml in men and 0.98 ng/ml in women; in about 60% the concentration was within the therapeutic range (0.80–2.00 ng/ml). The concentrations were clearly related to daily dose of digoxin. At equal dose levels old persons tended to have higher concentrations than younger persons. The interindividual variation in serum digoxin concentrations was very wide. However, when digoxin measurements in the same subjects were repeated about three months later, a good correlation between the two measurements was found. The interval between the last dose of digoxin and the collection of blood (up to 41 h) had relatively little effect on individual serum digoxin concentrations. Patients on concomitant thiazide or loop diuretic therapy had the same mean serum digoxin concentration as those not-receiving a diuretic. The mean concentration was significantly higher in patients taking a thiazide or loop diuretic combined with triamterene. The difference may have been due to an interaction between triamterene and digoxin.     

Impact of ABCB1 (MDR1) gene polymorphism and P-glycoprotein inhibitors on digoxin serum concentration in congestive heart failure patients

Digoxin, a drug of narrow therapeutic index, is a substrate for common transmembrane transporter, P-glycoprotein, encoded by ABCB1 ( MDR1 ) gene. It has been suggested that ABCB1 polymorphism, as well as co-administration of P-glycoprotein inhibitors, may influence digoxin bioavailability. The aim of the present study was to evaluate the effects of ABCB1 gene polymorphism and P-gp inhibitor co-administration on steady-state digoxin serum concentration in congestive heart failure patients. Digoxin concentrations as well as 3435C > T and 2677G > A,T ABCB1 single nucleotide polymorphisms, were determined in 77 patients administered digoxin (0.25 mg daily) and methyldigoxin (0.50 mg daily), some of them co-medicated with known P-glycoprotein (Pgp) inhibitors. Significant differences were noted in digoxin serum concentrations (C(min,ss)) between patients co-administered and not co-administered P-gp inhibitors: 0.868 +/- 0.348 and 0.524 +/- 0.281 for digoxin (p < 0.002), as well as 1.280 +/- 0.524 and 0.908 +/- 0.358 for methyldigoxin (p < 0.02), respectively. No influence of ABCB1 2677G > A,T and C3435C > T polymorphisms on digoxin concentration was noted. Although some of the previous studies have shown that digoxin pharmacokinetics might be affected by ABCB1 genetic polymorphism, those modest changes are probably clinically irrelevant, and digoxin dose adjustment should include P-gp inhibitor co-administration rather than ABCB1 genotyping.     

The effect of gender on the pharmacokinetics of verapamil and norverapamil in human

The effects of gender on the pharmacokinetics of verapamil and its active metabolite, norverapamil, following single oral dose (80 mg, Isoptin) to 12 healthy male (mean age: 25.75+/-2.42 years, mean body weight: 70.59+/-9.94 kg) and 12 healthy female subjects (mean age: 24.08+/-2.84 years, mean body weight: 56.67+/-5.23 kg) were investigated in the present study. Plasma concentrations of verapamil and norverapamil were analysed using a modified high-pressure liquid chromatography method. Pharmacokinetic parameters were calculated by non-compartmental analysis for each subject. For verapamil the half-life (t1/2) and mean residence time (MRT) were significantly shorter in women than men (p<0.01 and p<0.05, respectively). For other pharmacokinetic parameters of verapamil there were no significant differences between males and females. For norverapamil, t1/2, MRT and time to reach to the maximum plasma concentration (Tmax) showed statistically significant differences between the two genders. The AUC(0-24) and AUC(0-infinity) ratios of norverapamil to verapamil were also calculated. The ratios were significantly higher in women compared with men. These observations indicate that the elimination rate of verapamil is faster in women than men which may be attributed to the higher activity of CYP3A4 or lower activity of P-glycoprotein in women compared with men. A contribution of both factors in the appearance of gender differences in verapamil pharmacokinetics is also possible.     

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.     

Effect of zaleplon on digoxin pharmacokinetics and pharmacodynamics.

The pharmacokinetics and pharmacodynamics of digoxin alone and digoxin plus zaleplon were studied. Healthy, nonsmoking men between 18 and 45 years of age were given a single oral dose of digoxin 0.375 mg daily on days 1 through 9. On days 10 through 14, the subjects received digoxin 0.375 mg plus oral zaleplon 10 mg daily. Blood samples were obtained on days 3, 5, 8, 9, and 14, and serum digoxin concentration data were analyzed by model-independent pharmacokinetic methods. Blood pressure, heart rate, PR interval, and QTc interval were recorded to determine the effect of zaleplon on digoxin pharmacodynamics. A total of 20 men completed the study. Maximum serum digoxin concentration and area under the serum digoxin concentration-versus-time curve from 0 to 24 hours met bioequivalence test criteria. There were no significant differences in QTc or PR interval between days 9 (digoxin alone) and 14 (digoxin plus zaleplon), and there were no clinically important changes from baseline to the study's end in vital signs, physical examination findings, or ECG results for individual subjects. Eighteen percent of the subjects who received digoxin alone and 35% of those who received digoxin plus zaleplon reported one or more adverse effects; all were mild and resolved quickly. Zaleplon had no significant effects on selected pharmacokinetic and pharmacodynamic properties of digoxin.     

The effect of captopril on pharmacokinetics of digoxin in patients with mild congestive heart failure.

The effect of captopril on steady-state pharmacokinetics of digoxin was studied in 12 patients with mild congestive heart failure (CHF; New York Heart Association functional class 1 or 2). Serum and urine digoxin concentrations were determined before and after a repeated administration of captopril in the patients on chronic digoxin therapy. The patients were taking digoxin, 0.25-0.375 mg/day, once daily, and were concurrently administered captopril, 37.5 mg/day, three times daily, for seven days. Peak serum concentration of digoxin (SCD) before and after captopril was 2.1 +/- 0.2, mean +/- SEM, and 2.0 +/- 0.1 ng/ml; the time to peak was 1.1 +/- 0.2 and 1.8 +/- 0.3 h; the terminal half-life (t1/2 alpha) was 10.9 +/- 1.0 and 8.7 +/- 0.9 h, and the area under the concentration-time curve to 24 h was 26.9 +/- 2.4 and 27.6 +/- 2.0 ng.h/ml. There was no significant difference between patients without and with captopril in SCD and its pharmacokinetic parameters. Renal digoxin clearance and creatinine clearance also showed no significant difference. After an administration of captopril, angiotensin-converting-enzyme (ACE) activity was well suppressed. These results suggest that captopril does not increase SCD in patients with CHF, and effectively suppresses ACE activity. Thus, modification in the dosage regimen of digoxin may be unnecessary in the case of coadministration with captopril.     

Amiodarone does not affect digoxin kinetics in the rabbit

It has been reported that amiodarone may interact with digoxin in man. We investigated the effects of amiodarone pretreatment (35 mg kg-1 day-1) on the pharmacokinetics of a single dose of digoxin (50 micrograms kg-1) in 6 rabbits. Total body clearance of digoxin was 138.84 +/- 44.67 and 147.99 +/- 29.17 ml min-1, serum half life 187.9 +/- 60.9 and 181.34 +/- 25.57 min and volume of distribution 35.4 +/- 8.54 and 37.8 +/- 3.9 litres before and after amiodarone treatment, respectively. None of these changes were statistically significant. We conclude that the presence of an amiodarone-induced change in digoxin pharmacokinetics in the rabbit was not evident and that other animal models will be necessary for studying this interaction.     

Effects of grapefruit juice on intestinal P-glycoprotein: evaluation using digoxin in humans

STUDY OBJECTIVES: To determine the effects of grapefruit juice on the pharmacokinetics of oral digoxin, a P-glycoprotein substrate not metabolized by cytochrome P450 3A4, in healthy volunteers, and to assess whether polymorphic multidrug-resistance-1 (MDR1) expression contributes to interindividual variability in digoxin disposition. DESIGN: Prospective, open-label, unblinded, crossover study. SETTING: University research center. SUBJECTS: Seven healthy adult volunteers (four men, three women). INTERVENTION: Each subject received a single oral dose of digoxin 1.0 mg with water or grapefruit juice with at least a 2-week washout between treatments. During the grapefruit juice phase, juice was administered 3 times/day for 5 days before digoxin administration to maximize any effect on P-glycoprotein. MEASUREMENTS AND MAIN RESULTS: Digoxin pharmacokinetics in the presence and absence of grapefruit juice were compared. The MDR1 exon 26 C3435T genotype was determined by real-time polymerase chain reaction. Compared with water, grapefruit juice significantly reduced the digoxin absorption rate constant (3.0 +/- 2.4 to 1.2 +/- 1.0 hr(-1), p<0.05) and increased absorption lag time (0.32 +/- 0.12 to 0.53 +/- 0.34 hr, p<0.05). Grapefruit juice did not affect digoxin maximum concentration (Cmax), area under the curve (AUC), elimination half-life, or renal clearance. The effect of grapefruit juice on digoxin Cmax (-45% to +41%) and AUC(0-4) (-29% to +25%) varied substantially among subjects and was inversely correlated with the values during the water phase. Trends toward higher digoxin Cmax AUC, and absorption rate constant during the water phase were found in CC homozygotes compared with subjects carrying a T allele. CONCLUSION: Inhibition of intestinal P-glycoprotein does not appear to play an important role in drug interactions involving grapefruit juice. Interindividual variability in response to grapefruit juice may be related to the balance of intestinal drug uptake and efflux transport.     

The pharmacokinetics of piroxicam in elderly persons with and without renal impairment.

1. Piroxicam pharmacokinetics were assessed in three groups of subjects: (1) young healthy volunteers, (2) healthy elderly subjects (mean +/- s.d. creatinine clearance 88 +/- 13 ml min-1), and (3) elderly patients with renal insufficiency (creatinine clearance 60 +/- 10 ml min-1) following the administration of piroxicam 20 mg as a single dose and after chronic dosing of 20 mg once daily for 4 weeks. 2. Piroxicam and 5'-hydroxypiroxicam concentrations were measured by h.p.l.c. in serum and urine samples collected for 96 h after the single dose and for 144 h after chronic dosing. Unbound concentrations of piroxicam were determined by ultrafiltration. 3. Elimination half-lives, steady state concentrations of piroxicam and 5'-hydroxypiroxicam, clearances of total and unbound piroxicam, volumes of distribution normalized for body weight, and urinary recovery of 5'-hydroxypiroxicam were not influenced by age or renal function. Volumes of distribution after the single dose were significantly lower in women compared with men (mean +/- s.d. 10.0 +/- 2.9 l vs 12.9 +/- 5.0 l; 95% confidence interval of the difference 0.1 to 5.6). 4. Percent unbound piroxicam values were 1.46 +/- 0.3% after the single dose and 1.45 +/- 0.2% at steady state. There were significant reductions in clearance and clearance of unbound piroxicam between single and chronic doses. The half-lives of 5'-hydroxypiroxicam (80.9 +/- 44 h) were significantly longer than those of piroxicam (54.9 +/- 26 h) after chronic dosing.     

Steady state pharmacokinetics of tiaprofenic acid in elderly patients

Tiaprofenic acid (Surgam) steady state pharmacokinetics was investigated in eight elderly patients with three different dosage regimens: 200 mg twice daily, 400 mg twice daily and 200 mg three times daily. The following dose independent pharmacokinetic parameters were evaluated from a two-compartment open model; absorption lag time: 0.23 +/- 0.08 h, absorption rate constant: 4.32 +/- 0.51 h-1, distribution rate constant: 1.31 +/- 0.13 h-1 and elimination half-life: 4.66 +/- 0.42. An increase in dose produced a significant and proportional increase in tiaprofenic acid peak and trough serum concentrations at steady state. In contrast to the above mentioned dose independent parameters, the area under the serum concentration-time curve showed a small (12%), but significantly higher increase than expected when the dosage regimen was increased from 200 mg X 2 to 400 mg X 2. This was, however, considered to be of no clinical relevance. Anticipating a 19% reduction of tiaprofenic acid bioavailability due to the intake of food, approximations of total body clearance and apparent volume of distribution can be made to 30.0 +/- 2.0 ml/min and 11.8 +/- 2.0 l, respectively. In spite of the small disproportional increase (12%) observed in the area under the serum concentration-time curve, it can be concluded that tiaprofenic acid shows a well defined pharmacokinetics in old people with acceptable interindividual variations and with a fast building-up to constant and predictable steady state levels within the dosage regimens investigated. A linear relationship was demonstrated between creatinine clearance and tiaprofenic acid total body clearance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Study on the interaction of the dopamine agonist alpha-dihydroergocryptine with the pharmacokinetics of digoxin

AIM: The study was carried out to explore the potential for pharmacokinetic interaction of a single oral dose of alpha-dihydroergocryptine (CAS 14271-05-7, DHEC, Almirid) with digoxin. METHODS: The serum pharmacokinetics of digoxin were analysed after the administration of single oral doses of 0.5 mg digoxin administered either alone or concomitantly with 20 mg DHEC according to a randomised, non-blinded, two-period cross-over design, with study periods 2 weeks apart. Twelve healthy male subjects, 23 to 39 years of age were enrolled and were investigated in accordance with the protocol. Venous blood was sampled up to 48 h after dosing. Concentrations of digoxin in serum were determined by a competitive radioimmunoassay. RESULTS: The mean Cmax were 1.97 +/- 0.87 (after a median tmax of 1 h) and 2.05 +/- 0.95 ng/ml (after a median tmax of 0.83 h) after the administration of digoxin with (test) and without (reference) concomitant DHEC, respectively; the corresponding estimated treatment ratio for test: reference was 0.939, 95% CI: 0.781 to 1.129. The mean AUC(0-48) were 13.6 +/- 5.0 ng.h/ml and 13.3 +/- 4.7 ng.h/ml for the test and reference treatment, respectively; the corresponding estimated treatment ratio for test: reference was 1.011, 95% CI: 0.866 to 1.142. In addition, no clinically significant changes were observed by ECG monitoring. The tolerability of digoxin alone was good, significantly more adverse events occurred when co-administered with DHEC; these corresponded with the known adverse reaction profile and were of moderate intensity. No premature study termination was thus necessary. CONCLUSION: The present study did not demonstrate clinically relevant interaction of a single dose of DHEC on the pharmacokinetics of digoxin. On the basis of these observations there is no indication for an a priori adjustment of the dose of digoxin when concomitant treatment with DHEC is initiated.     

Influence of demographic factors on cyclosporine pharmacokinetics in adult uremic patients

The causes of variability in cyclosporine (CS) clearance (CL) are mostly unknown. The pharmacokinetics of CS were studied in 30 adult uremic patients after single intravenous and oral doses by analyzing serial concentrations in serum by radioimmunoassay (SR) and in whole blood by radioimmunoassay (WR) and high pressure liquid chromatography (WH). Bioavailability (F) and CL were calculated by noncompartmental models and were significantly different depending upon the assay method except for FSR = FWR: FSR = 43.2 +/- 21.7%; FWR = 43.5 +/- 18.5%; FWH = 36.4 +/- 17.3%; CLSR = 849 +/- 363 ml/min; CLWR = 380 +/- 156 ml/min; CLWH = 559 +/- 174 ml/min. The age of the patients and parameters describing body size such as weight, surface area and percent of ideal weight were not correlated with CL. The height of the patients correlated with CLWH but not CLSR or CLWR. Parameters responsible for CS binding in blood such as cholesterol, triglyceride, hemoglobin concentration or hematocrit did not explain variability in CL. Of the factors indicative of liver function alanine transaminase activity but not aspartate transaminase, lactate dehydrogenase, alkaline phosphatase activity nor total bilirubin concentration in serum was correlated with CL. F was not correlated with any of the demographic factors except for alanine transaminase. None of the significant correlations explained enough of the variability to afford a reliable prediction of CL or F.     

Interaction between digoxin and indomethacin or ibuprofen.

To study a potential interaction between digoxin and two non-steroid anti-inflammatory drugs, indomethacin (50 mg three times daily) and ibuprofen (600 mg three times daily) were given for 10 days to 10 and 8 patients, respectively, on chronic digoxin treatment. Serum digoxin measured by fluorescence polarisation immunoassay increased significantly (P less than 0.05) during treatment with indomethacin from pre-treatment values of 0.73 +/- 0.34 nmol l-1 (mean +/- s.d.) to a mean value of 1.02 +/- 0.43 nmol l-1, while administration of ibuprofen did not change the steady state serum concentration of digoxin. The result demonstrates that some non-steroidal anti-inflammatory drugs such as indomethacin increase serum digoxin to levels high in the therapeutic range. This should be taken into consideration when co-administering other drugs known to increase the serum concentration of digoxin such as several antiarrhythmics.     

Pharmacokinetic and pharmacodynamic aspects of concomitant mibefradil-digoxin therapy at therapeutic doses.

This study investigated the effect of mibefradil on digoxin pharmacokinetics an pharmacodynamics. Following a loading dose of digoxin (0.375 mg, three times, day 1), 0.375 mg was administered once daily to 40 healthy subjects (days 2-15). Mibefradil was administered daily at 50 mg, 100 mg, or 150 mg (days 9-15). With co-administration of 50 mg or 100 mg mibefradil (the recommended doses), mean digoxin Cmax values increased 1.19- and 1.32-fold, respectively; Cmin values were 0.95- and 1.04-fold, respectively; mean AUC0-24 h increased 1.05- and 1.11-fold, respectively; and the total amount of digoxin excreted in urine remained unchanged. Digoxin monotherapy produced modest but transient prolongations of PQ interval, small decreases in heart rate, and no changes in blood pressure. With the addition of mibefradil, no effects on trough blood pressure or cardiac index were observed, but there was a further increase in PQ interval and decrease in heart rate. In a previous study, mibefradil had no significant effect on trough plasma digoxin concentration in patients with congestive heart failure and ischemia. Therefore, while the vast majority of patients should not need their digoxin dosages adjusted when given mibefradil, an occasional patient may require dose reductions based on clinical response and plasma digoxin.