Pharmacokinetics of mepindolol in patients with chronic renal failure

Summary Sixteen young adult sufferers from extrinsic paroxysmal asthma with pollen hypersensitivity took part in a therapeutic trial of the synthetic anti-cholinergic agent oxitropium bromide administered by a metered dose inhaler. The study comprised three 3-week periods. The first, run-in period was carried out to confirm the ability of the patients to maintain a daily record of symptoms. During the second and third periods, the patient received 3 × 2 inhalations of drug or placebo in a cross-over design. The medical staff was blind to the nature of the aerosol (drug or placebo), which was given in random order. The run-in clinical score was high. Asymptomatic days were relatively infrequent and daily drug consumption was high. Functional studies between the cross-over periods showed flow-rate values close to normal, with an increase in residual volume and functional residual capacity. During treatment either with placebo or oxitropium, there was a statistically significant decrease in clinical scores. Results for oxitropium bromide treatment were significantly better than the run-in values (p<0.005) and the placebo period (p<0.02). There was no significant change in non-trial drug consumption. Functional values showed no difference in terms of flow rate, although oxitropium did cause a significant improvement in the RV/TLC ratio (p<0.05). No adverse reactions were reported.     

Pharmacokinetics of quinine in patients with chronic renal failure

Methods: We investigated the pharmacokinetics of quinine (Qn) following administration of a single oral dose of 600 mg Qn sulphate in six male Thai patients with a moderate degree of chronic renal failure (CRF), and six male Thai subjects with normal renal function. Results: The drug was well tolerated in both groups of subjects; no major adverse reactions were observed. A marked alteration in the pharmacokinetics of Qn was found in patients with CRF compared to healthy subjects; there were six signifiicant changes in the pharmacokinetic parameters. Absorption was delayed, but increased in CRF (t_max 4.5 vs 1.6 h, C_max 6.17 vs 3.45 g·ml^–1). Total clearance was significantly reduced 0.94 vs 2.84 ml·min^–1·kg^–1, whereas V_z/f remained unchanged (1.82 vs 2.78 1·kg^–1). This resulted in the increased values of AUC and prolongation of the t_1/2z and MRT in the patients (AUC 181.5 vs 61.8 g·min^–1·ml^–1, t_1/2z 26 vs 9.7 h, MRT 36.4 vs 11.3 h). Median concentrations of plasma unbound fraction of Qn collected at 4 h after drug administration in patients and healthy subjects were 7.3 vs 9.8%, respectively.     

Pharmacokinetics and antidiuretic effect of high-dose desmopressin in patients with chronic renal failure

High-dose desmopressin shortens the bleeding time in uraemia. The aim of this study was to investigate the pharmacokinetics and the antidiuretic effect of desmopressin when given in a dose normally used for haemostasis to patients with reduced renal function. Ten patients with chronic renal failure of varying aetiology were enrolled in the study. The age was 58 (20-76) years (median and range), serum creatinine 447 (309-691) micromol/l and plasma clearance of iohexol 16 (8-19) ml/min./1.73 m2 body surface. After baseline measurements, desmopressin was infused at a dose of 0.3 microg/kg. The plasma concentration of desmopressin was followed for 26 hr during and after the infusion and the pharmacokinetic parameters were estimated by compartmental analysis. Urine volume and osmolality, as well as body weight, blood pressure, heart rate, haematocrit, serum osmolality, electrolytes and creatinine, were measured repeatedly during the day before and for two days after the infusion. The total clearance of desmopressin was 0.35 (0.21-0.47) ml/min./kg, the volume of distribution at steady state was 0.30 (0.17-0.38) l/kg and the terminal half-life 9.7 (8.4-16) hr. After administration of desmopressin, urine osmolality increased significantly, by approximately 10%, and this increase lasted for 48 hr. Concomitantly, there was a modest but significant decrease in haematocrit. Thus, the clearance of desmopressin was on average decreased to approximately one quarter, and the terminal half-life was prolonged 2-3 times in the patients as compared to previously published values for healthy adults. The single haemostatic dose of desmopressin given to patients with severe renal failure did not cause fluid overload or changes in serum electrolytes.     

Pharmacokinetics of verapamil in patients with renal failure

Summary The pharmacokinetics of verapamil was studied in patients with end-stage chronic renal failure and in normal subjects after i.v. injection of 3 mg and a single oral dose of 80 mg. Plasma levels of verapamil and its active metabolite norverapamil were measured by HPLC. After i.v. injection, the terminal phase half-life and total plasma clearance of verapamil in both groups were similar. Haemodialysis did not change the time course of plasma verapamil levels after i.v. administration. After a single oral dose, the plasma levels of verapamil and norverapamil in both groups of subjects were similar. Subsequently, normal volunteers and patients with renal failure were treated for 5 days with oral verapamil 80 mg t.d.s. There was no difference between the 2 groups of subjects in the trough and peak levels of verapamil or of norverapamil. Intravenous and oral administration of the calcium channel blocking agent had similar effects on blood pressure, heart rate and the PR-interval in the electrocardiogram in both groups. The study demonstrated that the disposition of verapamil was similar in normal subjects and in patients with renal failure.Some of the results were presented at the Joint Spring Meeting of the German Pharmacological and Physiological Societies in Mainz, 1983 (Schols et al. 1983)     

Pharmacokinetics of ranitidine in patients with renal failure

The pharmacokinetics of ranitidine were studied in ten patients with renal failure (creatinine clearance, 6-54 mL/min) after intravenous (IV) (50 mg) and oral doses (150 mg). After oral administration, peak plasma concentrations of 378-808 ng/mL were obtained in two to six hours. Plasma concentrations declined very slowly and concentrations greater than 100 ng/mL were obtained for 16 to 20 hours after the dose. The elimination half-life following oral administration was 8.5 +/- 2.8 hours (standard deviation [SD]), and the bioavailability of ranitidine was 43.3% +/- 10.5%. After IV administration, the elimination half-life, plasma clearance, renal clearance, and volume of distribution were 7.0 +/- 1.0 hours, 170 +/- 38 mL/min, 36.0 +/- 25.0 mL/min, and 1.3 +/- 0.4 L/kg, respectively. About 20% of the IV dose and 9% of the oral dose were recovered unchanged in urine. There was a significant correlation between the renal clearance of ranitidine and creatinine clearance (r = .74, P less than .05) after IV administration. The elimination half-life in patients with renal insufficiency is about three times greater than that reported in the literature for healthy subjects. Similarly, the plasma clearance in these patients is about 20% of that reported in healthy subjects. The results indicate that ranitidine elimination is appreciably reduced in renal failure and that an adjustment of dose in patients with renal failure is warranted. A dose of 75 mg bid may be adequate in maintaining the therapeutic plasma concentrations that are required for adequate H2-blocking activity.     

Pharmacokinetics of iloprost in patients with chronic renal failure and on maintenance haemodialysis.

Iloprost is a potent, chemically stable prostacyclin-mimetic for which therapeutic efficacy has been proven in patients with peripheral arterial occlusive disease (PAOD) and in those suffering from Raynaud's phenomenon. In volunteers and PAOD-patients the pharmacokinetics of iloprost after intravenous (i.v.) infusion treatment was characterized by dose-dependent steady-state plasma levels, a terminal half-life of approximately 20-30 min, and a total clearance of 15-20 ml/min/kg. Bioinactivation was mainly due to beta-oxidation. In the present study the pharmacokinetics of iloprost was investigated in 21 patients suffering from renal insufficiency, which either required haemodialysis or not. They were treated by one hour i.v. infusion with 1 ng/kg/min and blood samples were taken during and after the end of infusion. Due to technical sampling problems iloprost pharmacokinetics could only be calculated for seven dialysis and eight non-dialysis patients. In the dialysis patients steady-state levels were 114 to 320 pg/ml as compared to 36 to 70 pg/ml in the non-dialysis group. Half-lives were similar in both groups: alpha-phase: 0.05 h and beta-phase: 0.5 h. The total clearance was 2.6 to 8.0 ml/min/kg (dialysis patients) and 13.2 to 25.8 ml/min/kg (non-dialysis patients). The present study demonstrated that the pharmacokinetic profile of iloprost in patients with renal failure (not subject to haemodialysis) was similar to that observed in PAOD-patients and volunteers. In patients on maintenance haemodialysis, iloprost clearance was reduced by a factor of four. The iloprost dose regimen required in general (due to interindividual variability in response) a careful dose titration.     

Pharmacokinetics of tocainide in patients with severe renal failure

Summary The plasma levels of tocainide have been followed after oral administration of 600 mg p.o. to 20 patients with renal failure due to various causes, and to 8 healthy controls. The peak plasma concentrations in the patients with pyelonephritis (3.80 µg/ml) and interstitial nephritis (3.74 µg/ml) but not in those with glomerulonephritis (3.17 µg/ml) differed from that in healthy volunteers (3.24 µg/ml). The renal clearance of tocainide was well correlated with the endogenous creatinine clearance and was dependent on urine pH. No difference in renal clearance was observed between the patients groups. It is suggested that the changes in plasma levels are a consequence of decreased renal clearance. Creatinine clearance was shown to be a poor estimator of tocainide clearance, which suggests that extrarenal clearance plays an important role in the handling of the drug in the body. The findings are used to suggest a safe dosage regimen.     

Pharmacokinetics of oral diltiazem and five of its metabolites in patients with chronic renal failure

The pharmacokinetics of oral diltiazem were studied in 10 patients with chronic renal failure not requiring dialysis and in five healthy volunteers after a single dose of 120 mg. We found that patients with chronic renal failure had lower amounts of unchanged diltiazem and of its main metabolite (MA) in urine and a trend to have slightly higher values of plasma concentration. Since the terminal elimination phase is not affected by chronic renal failure we conclude that this trend is probably the result of alterations in the volume of distribution of diltiazem in these patients.     

Pharmacokinetics of tinidazole in chronic renal failure and in patients on haemodialysis.

The pharmacokinetics of tinidazole after infusion (800 mg in 15 min) were studied in 12 patients with chronic renal failure (RI) and in five patients undergoing regular dialysis treatment (RD). Tinidazole elimination plasma half-life was 15.09 +/- 0.68 h (mean +/- s.e. mean) (RI) and 12.9 +/- 1.0 h after dialysis (RD), but there was a significant decrease in half-life during dialysis (4.25 +/- 0.43 h) P less than 0.001). The apparent volume of distribution (0.64 +/- 0.03 l/kg) was equal to extra and intracellular water volume and tinidazole was little bound to plasma protein (8%). There was a slight sex difference in apparent volume of distribution between male patients (0.70 +/- 0.09 l/kg) and female patients (0.59 +/- 0.10 l/kg) (P = 0.07), but as body clearance decreases in the same order, there was no modification of plasma half-life. In renal failure, pharmacokinetics of tinidazole were not disturbed because no correlation between half-life, body clearance and creatinine clearance occurred; urine elimination was about 7% of administered dose. Plasma clearance during dialysis was 49.9 +/- 3.2 ml/min and about 43% of the available drug was eliminated during the 6 h dialysis procedure. These results suggest that an additional half-dose infusion should be given after the end of dialysis in patients undergoing regular dialysis treatment.     

头孢噻甲羧肟在肾功能衰竭血液透析病人的药物动力学

本文采用高效液相色谱法测定6例肾衰尿毒症病人在接受维持性血液透析过程中头孢噻甲羧肟的血药浓度。2g 单剂量静脉给药后,经4h 的血液透析,血药浓度由134.4±34.5μg/ml 降至43.2±7.3μg/ml,平均下降67.0±5.1%。透析半衰期为5.0±2.2h,透析清除率为3.8±1.1L·h~(-1),分布容积为24±5L。结果表明,通过血液透析可清除病人体内的头孢噻甲羧肟。     

Pharmacokinetics of intravenous vancomycin in patients with end-stage renal failure

The pharmacokinetics of a 500-mg dose of i.v. vancomycin were studied in six Chinese patients with end-stage renal failure. Serum vancomycin concentrations were determined by high-performance liquid chromatography. Observed peak and trough (at 168 h postinfusion) concentrations were in the range of 14.2-35.0 micrograms/ml and 2.8-5.5 micrograms/ml, respectively. The data were analyzed using the PCNONLIN. In all six patients, the data could be fitted well by both the biexponential and triexponential models, but in three patients the latter model provided a better fit. Two-compartment pharmacokinetic parameters obtained from the six patients were t 1/2 alpha 1.13 +/- 0.25 h (mean +/- SEM), t 1/2 beta 121.3 +/- 8.2 h, Vc 0.45 +/- 0.09 L/kg, Vss 1.00 +/- 0.12 L/kg, ClT 5.90 +/- 0.69 ml/kg/h, and the calculated Cmax 25.0 +/- 6.1 micrograms/ml. The mean vancomycin serum protein binding was 18.5 +/- 12.0% as compared with a mean of 46.0% in pooled serum from normal controls. Hemodialysis had no significant effect on vancomycin protein binding or clearance. On the basis of our kinetic study, 500 mg of vancomycin given every seven days is probably adequate treatment for methicillin resistant Staphylococcus aureus infection in end-stage renal failure patients, but further clinical studies are necessary to confirm this.     

Pharmacokinetics of meropenem in patients with renal failure and patients receiving renal replacement therapy

Meropenem is a well established carbapenem antibacterial with a wide spectrum of activity against Gram-positive and Gram-negative bacteria, including beta-lactamase producers and Pseudomonas aeruginosa. Because of its clinical and bacteriological efficacy, meropenem is an important antimicrobial drug in the treatment of serious infections in adults and in children. Meropenem is predominately excreted unchanged in the urine, and thus dosage adjustments are necessary in patients with renal insufficiency and those undergoing intermittent haemodialysis (IHD) or various forms of continuous renal replacement therapy (CRRT), such as continuous venovenous haemodialysis, continuous venovenous haemodiafiltration (CVVHDF), continuous venovenous haemofiltration (CVVHF) or continuous ambulatory peritoneal dialysis (CAPD). The half-life of meropenem (approximately 1 hour in healthy volunteers) is prolonged up to 13.7 hours in anuric patients with end-stage renal disease. In patients receiving renal replacement therapy, half-life is influenced by drug-specific factors as well by membrane and treatment modalities (IHD, CRRT or CAPD). Plasma meropenem concentrations reach a peak of between 53 and 62 mg/L after the administration of meropenem 1g intravenously to healthy volunteers, up to 53 mg/L after meropenem 0.5g in haemodialysis patients, and between 18 and 45 mg/L after meropenem 1g during CRRT in critically ill patients. Approximately 50% of meropenem is eliminated by IHD, 25 to 50% by CVVHF and 13 to 53% by CVVHDF. Such differences are not negligible and demonstrate the great influence of the treatment modality on the elimination of the drug during renal replacement therapy. Thus, physicians run the risk of underdosing with this antimicrobial drug because of the quite different recommendations in the literature. Because of the excellent tolerability profile of meropenem, such underadministration should be avoided.     

卡维地洛对慢性心衰合并肾功能不全患者肾功能的影响

目的:评价卡维地洛对慢性心衰(CHF)合并慢性肾功能不全(CRF)患者肾功能的影响。方法:入选27例CHF合并CRF患者,在充分抗心力衰竭治疗的基础上,加用卡维地洛,观察不同阶段左室射血分数(LVEF)和肾功能的变化。结果:卡维地洛治疗后,LVEF在治疗3个月后开始升高,12个月后显著高于基线水平(p<0.01)。治疗后1个月,血肌酐(Scr)升高(p<0.05),3个月时回落到基线水平以下(p<0.05),12个月时仍低于基线水平(p<0.05);治疗后1个月,内生肌酐清除率(Ccr)先轻度下降(p<0.05),3个月时回升高于基线水平(p<0.01),12个月时仍显著高于基线水平(p<0.01)。卡维地洛对尿微量白蛋白和24h尿蛋白定量影响不大(p>0.05)。结论:第三代β-受体阻滞剂卡维地洛,可改善慢性心衰合并慢性肾功能不全患者的心功能,早期引起肾功能的轻度降低,随后肾功能显著改善。     

Pharmacokinetics of intraperitoneal teicoplanin in patients with chronic renal failure on continuous ambulatory peritoneal dialysis.

The pharmacokinetic profile of teicoplanin, a new glycopeptide antibiotic active against Gram-positive aerobic and anaerobic bacteria, is described in five patients with end-stage renal disease on continuous ambulatory peritoneal dialysis (CAPD). A single 3 mg kg-1 dose was given intraperitoneally in the dialysate during a 6 h dwell time. The drug appeared in the plasma within 15 min at 1.00-0.28 mg l-1 (mean +/- s.d. = 0.70 +/- 0.45) in all five subjects, and peak serum concentrations ranged from 5.53 to 2.80 mg l-1 (4.84 +/- 1.43) at 6 h. Approximately 70% (71 +/- 12) of teicoplanin was absorbed from the peritoneal dialysis fluid during a single 6 h dwell time. The rate constant for peritoneal transfer (lambda d) averaged 0.318 h-1 and the half-life (t1/2 lambda d) was 2.18 h. Further values were serum elimination half-life 114-173 h; total body clearance 263-532 ml h-1; steady-state volume of distribution 68-93 l. This drug profile closely agrees with data reported after intravenous injection in patients on CAPD and suggests that teicoplanin has bidirectional exchange characteristics through the peritoneal membrane, although transfer from the systemic circulation to peritoneal fluid is consistently low. Instillation of teicoplanin in CAPD fluid may be a useful route of administration for treatment of peritonitis and exit site infections in CAPD patients.     

Pharmacokinetics of acebutolol in patients with all grades of renal failure

Summary The pharmacokinetics of acebutolol was studied in 10 healthy subjects with normal renal function (RN), in 13 patients with various degrees of renal failure (RI) and in 8 patients undergoing repeated haemodialysis (RD). A highly specific method was used to measure acebutolol (A) and N-acetylmetabolite (NAM). In RN the decrease in plasma levels was biexponential with an apparent plasma half lives in the slow phase of A: 8.8±2.3 h and NAM: 11.4±2.2 h. The percentage of the dose excreted unchanged was 13.9% and as NAM 25.8%. Renal clearances were A: 167±20 ml/min and NAM: 150±18 ml/min. The apparent plasma half life of acebutolol does not change according to the degree of renal insufficiency (RI: 7.0±2.7 h, RD: 7.5±2.7 h), while that of NAM is increased (RI: 21.5±10.1 h, RD: 32.3±16.8 h). There is a linear relationship between the apparent elimination rate constant of NAM and creatinine clearance (r=0.832,p<0.001). In RI 21.7% of the dose is excreted in urine (A 5.0%, NAM 16.7%). When renal function is impaired, the renal clearance of A and NAM decrease in parallel with the creatinine clearance (A: r=0.874,p<0.001; NAM: r=0.954,p<0.001). During dialysis the plasma half life fell (A=3.4±0.9 h, NAM=7.4±2.6 h). The dialytic clearance was A: 42.6±12.7 ml/min and NAM: 40.4±16.3 ml/min, for a blood flow of 238±35 ml/min through a dialyser with a cuprophane membrane (Ultraflo II Travenol). Acebutolol is taken up by erythrocytes (_bc=0.50±0.04). The results suggest that the dosage of acebutolol should be adjusted according to the degree of renal insufficiency.     

Pharmacokinetics and dynamics of famotidine in patients with renal failure.

1. Famotidine, a new histamine H2-receptor antagonist was administered intravenously (20 mg) to 22 patients with end stage renal disease during a dialysis free interval (n = 6) and during different blood purification processes including haemodialysis (HD; n = 4), intermittent haemofiltration (HF; n = 4), continuous haemofiltration (CHF; n = 4) and continuous ambulatory peritoneal dialysis (CAPD; n = 4). The plasma, the dialysate/filtrate and the urine concentrations of famotidine were analysed by h.p.l.c. 2. In addition, intra-gastric pH was measured by a long-term-pH probe in seven patients with renal failure and in six patients with normal renal function (control group) following 20 mg famotidine. 3. A 7 to 10 fold prolongation of famotidine's elimination half-life (27.2 +/- 8.5 h; mean +/- s.d.) was observed in patients with renal failure as compared with the half-life (2.6-3.6 h) in subjects with normal renal function. 4. Total body clearance (CL) and volume of distribution (V) were found to be 33.5 +/- 10.1 ml min-1 and 1.3 +/- 0.7 l kg-1, respectively in patients with end-stage renal failure. 5. Blood purification processes have shown considerable variation in clearing famotidine from the body: 16.4 +/- 8.9 and 6.0 +/- 2.9% of the administered dose in HD with polysulphone and cuprophan membranes respectively, 7.7 +/- 5.2% in HF with a polyacrylonitrile membrane (each for 5 h), 4.5 +/- 1.1% in CAPD and 16.2 +/- 4.9% in CHF with a polysulphone membrane within 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)     

Teicoplanin pharmacokinetics in patients with chronic renal failure

The pharmacokinetic profile of teicoplanin, a new glycopeptide antibiotic active against Gram-positive aerobic and anaerobic bacteria, was studied in 5 healthy male volunteers and 29 adult patients with various degrees of renal impairment, given a single 3 mg/kg intravenous dose. Teicoplanin was assayed in plasma and urine specimens by a microbiological method. Pharmacokinetic parameters for teicoplanin were estimated both by a 3-compartment open pharmacokinetic model and by non-compartmental analysis. Elimination half-life increased with the decrease in creatinine clearance and mean values ranged from 41 hours in volunteers to 163 hours in anuric patients. Renal failure did not affect either the volume of distribution of the central compartment (mean approximately 0.09 L/kg) or the steady-state volume of distribution (mean approximately 0.9 L/kg). Both total and renal clearance decreased with severity of disease, particularly the latter, while non-renal clearance was unaffected by renal failure. Average values were from 19 to 6 ml/min for total clearance and from 12 to 0.4 ml/min for renal clearance. There was a linear correlation between the total clearance of teicoplanin and creatinine clearance, as well as between renal clearance and creatinine clearance. The total urinary excretion of active teicoplanin averaged 65% of the administered dose in normal subjects, but was significantly reduced in the presence of renal insufficiency. Guidelines for administration of teicoplanin in patients with renal failure are given.