Pharmacokinetics of torasemide and its metabolites in healthy controls and in chronic renal failure

Summary The pharmacokinetics of 20 mg torasemide i.v. has been studied in 7 healthy controls and 9 patients with varying degrees of renal impairment.Torasemide had a t_1/2 of about 4 h which was independent of kidney function, as the nonrenal clearance of torasemide was 3-times greater than its renal clearance. The active metabolite M1 and the main metabolite M5 were accumulated in chronic renal failure.In contrast to liver function, therefore, kidney failure does not have an important effect on the pharmacokinetics of torasemide.     

Pharmacokinetics of carteolol in patients with impaired renal function

Summary In order to determine the appropriate dosage of carteolol in renal dysfunction, the pharmacokinetics of carteolol has been examined in appropriate patients. The plasma concentrations and urinary excretion of carteolol were investigated in 15 patients with varying degrees of renal impairment during the administration of 5–20 mg carteolol hydrochloride (5 mg/tablet) for 2–45 months.Plasma carteolol levels were linearly correlated with the serum creatinine concentration (r = 0.87) and reciprocally with the creatinine clearance (r = 0.82). The urinary carteolol concentration was correlated with the urinary creatinine concentration (r = 0.69) and the urinary carteolol excretion was also correlated with the creatinine clearance (r = 0.79). These relationships become even closer when the plasma carteolol concentrations and urinary excretion rate of carteolol were factored by the administered tablets. The fractional renal excretion of carteolol was virtually constant at various degress of renal function, and it always exceeded 100%, which indicates that carteolol was actively secreted, even in patients with renal failure. The estimated tubular secretion rate of carteolol was logarithmically correlated with the fractional renal excretion of carteolol (r = 0.93).The results indicate that the dose of carteolol should be determined according to the degree of renal impairment.     

慢性肾衰患者血液透析时司帕沙星的药物动力学

目的 观察司帕沙星在慢性肾衰患者血液透析时的药物动力学特征.方法 用高效液相色谱法测定透析和非透析住院患者单剂量口服司帕沙星后血清和尿药物浓度,并计算药物动力学参数.结果 经PKNP-N_1药代动力学软件摸拟和计算,司帕沙星的药物动力学符合一级吸收二室开放模型,主要药动学参数:透析时T_(1/2(ka))=(1.25±0.57)h,T_(1/2β)=(11.88±4.13)h,T_(peak)=(4.18±0.78)h,C_(max)=(0.80±0.17)mg·L~(-1),AUC_(0~∞)=(6.90±3.25)mg·h·L~(-1)尿中24h原形药物排除率为(8.98±3.92)%;未透析时T_(1/2(ka))=(1.12±0.42)h,T_(1/2β)=(15．93±5．20)h,T_(peak)=(3.88±0.75)h,C_(max)=(0.69±0.37)mg·L~(-1),AUC_(0~∞)=(10.05±4.13)mg·h·L~(-1),尿中24h原形药物排出率为(10.58±5.64)%.结论 司帕沙星在慢性肾衰患者血液透析时消除加快.     

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 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 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.     

慢性肾功能衰竭患者环丙沙星药物动力学研究

对８例健康志愿者，１１例慢性肾功能衰竭患者（Ｃｃｒ＜１０ｍｌ／ｍｉｎ）静脉恒速滴注乳酸环丙沙星２００ｍｇ（３０ｍｉｎ）注射液后的临床药物动力学进行了研究，用高效液相色谱法对血清中环丙沙星进行测定，主要药动学参数分别是滴注完时浓度Ｃｏ健康人组为２．２６ｍｇ／Ｌ，未透析组为２．５２ｍｇ／Ｌ，血透组为２．３７ｍｇ／Ｌ，腹透组为２．３５ｍｇ／Ｌ。清除相半衰期健康人为２．７±０．８ｈ，未透析组为１５±４ｈ，血透组为５．０±１．９ｈ，腹透组为６．３±２．７ｈ。表明慢性肾功能衰竭患者的环丙沙星药物动力学过程较健康者有明显的改变，根据以上数据提出慢性肾功能衰竭时的一些给药方案     

Pharmacokinetics of flutamide in patients with renal insufficiency

AIMS: The aim of this study was to determine the pharmacokinetic parameters of flutamide, a nonsteroidal antiandrogenic compound, and its pharmacologically active metabolite, hydroxyflutamide, in renal insufficiency. Haemodialysis (HD) clearance of flutamide and hydroxyflutamide was also determined. METHODS: Pharmacokinetic parameters were assessed for flutamide and hydroxyflutamide in 26 male subjects with normal renal function (creatinine clearance by 24 h urine collection, CLcr, greater than 80 ml min(-1) 1.73 m(-2); n=6) or reduced renal function; CLcr=50-80 (n=7), 30-49 (n=3), 5-29 (n=4), and <5 ml min(-1) 1.73 m(-2)-HD (n=6), following a single, oral 250 mg flutamide dose. Subjects undergoing HD received a second 250 mg dose of flutamide 4 h prior to HD; blood and dialysate were collected during HD to determine dialysability of flutamide and hydroxyflutamide. RESULTS: Cmax, tmax, AUC, t1/2, and renal clearance of flutamide and hydroxyflutamide did not differ between groups. Less than 1% of the dose appeared in dialysate as hydroxyflutamide. No serious adverse events were observed. CONCLUSIONS: Renal function did not affect flutamide nor hydroxyflutamide disposition. HD did not alter hydroxyflutamide pharmacokinetics. Dosing adjustments for renal impairment or HD are not indicated for flutamide.     

Antipyrine metabolite formation and excretion in patients with chronic renal failure

Summary In the present study the influence of chronic renal insufficiency on antipyrine clearance, metabolite formation and excretion was investigated in 8 patients. After oral administration of antipyrine, the parent compound, its metabolites and their conjugates were assayed in plasma and urine. Besides the parent drug, 3-hydroxymethylantipyrine (HMA) was present in plasma in the free and conjugated forms, whereas 4-hydroxyantipyrine (OHA) and norantipyrine (NORA) were found only in the conjugated form. The same was true for urine. The plasma concentrations of these metabolites are too low to be measured in subjects with normal renal function.Plasma antipyrine clearance in the patients was in the same range as in healthy subjects. Investigation of metabolite kinetics, however, revealed that the rate of formation of NORA was preferentially decreased, whereas that of OHA and HMA were unaltered. Renal clearance of the metabolites of antipyrine was severely impaired in patients with renal insufficiency, and the resulting accumulation made it possible for the first-time to measure the antipyrine metabolites in plasma. Mean residence times of metabolites were longer than that of the parent compound. Renal clearances of the conjugates were correlated with the creatinine clearance, but were somewhat higher. Renal clearance of free HMA was lower and was also correlated with creatinine clearance.The mean clearance for glucuronidation of HMA was 93.1 ml/min. The results suggest that in healthy subjects Phase I metabolism is the rate-limiting step in the elimination of antipyrine, which is essential for its application as a model drug in metabolism studies.     

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 the loop diuretic piretanide in renal failure

Summary Piretanide 60 mg was administered intravenously over 30 min to 15 men with different degrees of renal failure. The mean piretanide serum concentration at the end of the infusion period was 5.72±1.51 µg/ml. Serum piretanide concentration-time curves declined biexponentially and 24 hours after medication the serum level had fallen to less than twice the detection limit. The terminal half-life ranged from 1.63 to 3.44 h. A relationship to creatinine clearance was not demonstrable. The mean metabolic clearance of piretanide was 107.7±47.6 ml/min/1.73 m² body surface area and was the same as that reported for healthy subjects. The renal clearance of piretanide ranged from 3.33 to 43.9 ml/min/1.73 m² body surface area and very closely correlated with the creatinine clearance (p<0.01). Its renal clearance dependend principally on active secretion of the drug into the tubule, and glomerular filtration appeared unimportant. There was a close relationship between the amount of piretanide excreted in the urine and the creatinine clearance. Because the diuretic effect of piretanide depends on the concentration of the drug in the tubule, the observed correlation might be of use in evaluating the appropriate dosage of piretanide in patients with renal failure. The present data suggest that single daily doses of piretanide will not result in accumulation, even when high doses are administered to patients with advanced renal failure.     

Pharmacokinetics of sotalol after chronic administration to patients with renal insufficiency

Summary Ten hypertensive patients with moderate to severe impairment of renal function were treated with sotalol for 5 to 10 weeks (average 6.4 weeks). Dosage was individually titrated (range 80 to 480 mg daily). The drug was given once daily in the morning. In eight patients blood pressure was satisfactorily controlled. Higher steady-state levels were observed than have been reported after similar doses in patients with normal renal function. The apparent first-order elimination rate constant and plasma clearance were significantly correlated with glomerular filtration rate. For an anuric patient, serum half-life was calculated to be 69 h. In relation to the raised plasma levels, side effects were uncommon. Since sotalol is excreted predominantly via the kidney, therapy in patients with impaired renal function should start with a low dose and any increase in dosage should be made carefully. As the anti-hypertensive effect does not appear to be correlated with the plasma level or with tolerance, adjustment of dose should be based on clinical response.     

Pharmacokinetics of flecainide in patients with mild and moderate renal failure compared with patients with normal renal function

Summary We have studied the pharmacokinetics of flecainide after the oral administration of 100 mg to 8 patients without renal impairment and 8 patients with mild to moderate renal failure. Both groups gave comparable results with respect to the peak plasma concentrations and the time to peak. There was a significant correlation between renal flecainide clearance and endogenous creatinine clearance. The elimination half-time in the patients with impaired renal function was significantly longer (19.9, SD 9.9 h) than that in the patients with normal renal function (11.5, SD 4.2 h), but the variability in the elimination half-time in renal failure could not be explained on the basis of the available results.dedicated to Professor Dr. U. Geßler on the occasion of his 65th birthday     

Pharmacokinetics of nitrendipine in terminal renal failure

Summary The pharmacokinetics and plasma protein binding of nitrendipine in patients with terminal renal failure have been compared with those in subjects with normal renal function.Kinetic parameters were calculated after a single 40 mg oral dose, an i.v. injection of 3 mg and after a 15 mg i.v. infusion of nitrendipine. Steady-state plasma levels were determined after 5 days of oral treatment with 20 mg b.d.Pharmacokinetic parameters and steady-state plasma levels in patients with renal failure did not differ from those in subjects with normal renal function.Nitrendipine was as highly bound to plasma proteins in patients with renal failure, as in subjects with normal renal function. The plasma protein did not differ between the two.The dosage of nitrendipine need not be modified for kinetic reasons in patients with renal failure.     

Pharmacokinetics of isosorbide-5-nitrate in renal failure

Summary The pharmacokinetics of the antianginal drug isosorbide-5-nitrate (IS-5-N) was studied in 20 patients with varying degrees of chronic renal failure after repeated oral doses of standard 20 mg tablets t.d.s. Blood samples were taken in the steady state on the 2nd and 28th days, and the plasma level was assayed by HPLC. There was no statistically significant difference in C _max ^ss , t_1/2 and AUC _0–8 ^ss between the 2nd and 28th days, nor was a difference found between patients with mild and severe renal failure.     

伴有重度肾功能不全的慢性肾小球肾炎患者可以应用依那普利吗？

目的 探讨依那普利对伴有重度肾功能不全的慢性肾小球肾炎患者的有效性和安全性.方法慢性肾小球肾炎患者46例,以内生肌酐清除率(Ccr)分为两组.高Ccr组Ccr 50 ml·min-1以上,13例;中Ccr组Ccr 25～50 ml·min-1,17例;低Ccr组Ccr 25 ml·     

Elimination and haemodynamic effects of nitrendipine in patients with chronic renal failure

Summary In sixteen patients with arterial hypertension and differing degrees of renal function the pharmacokinetics and haemodynamic effects of nitrendipine have been studied after treatment for 7 days. The AUC (0–24) and the elimination half-life of nitrendipine were significantly increased; the AUC (0–24) in patients with renal failure (median creatinine clearance 27.1 ml × min^–1) was 196 ng × ml^–1 × h compared to 97.8 ng × ml^–1 × h in control subjects (median creatinine clearance 94.4 ml × min^–1). The corresponding elimination half-lives were 13.5 h in renal failure and 4.4 h in the controls. The haemodynamic effects of nitrendipine were not enhanced in the patients.     

Pharmacokinetics of practolol in renal failure

Summary The effect of renal failure on the excretion of oral doses of practolol has been studied. The plasma half-life increased up to 6.6 times normal and the cumulative urinary excretion of the drug was reduced. There was a linear correlation between the overall elimination rate constant of practolol and inulin and creatinine clearances. A linear correlation was also found between the renal clearances of practolol and inulin. The dose of practolol required for maintenance therapy should be reduced in patients with impaired renal function.The results have been presented in part as a thesis for the M.D. degree of the University of Giessen.     

A pharmacokinetic study of prazosin in patients with varying degrees of chronic renal failure

Summary Pharmacokinetic parameters of prazosin (t_1/2, t_max, C_max and AUC have been studied in 18 hypertensive patients with varying degrees of chronic renal failure (serum creatinine ranging from 1.6 to 11.4 mg/dl). An oral dose of 2 mg of prazosin was added to the preexisting antihypertensive medication. The degree of renal impairment did not influence the peak drug concentration, the time to peak or the serum half-life. On the other hand, the hypotensive action after 2 mg prazosin, was more pronounced in patients with severe chronic renal failure. This effect could not be explained by a difference in the pharmacokinetics of prazosin in severe as compared to moderate chronic renal failure or to normal renal function.     

慢性肾功能不全患者血浆同型半胱氨酸水平检测

目的：研究慢性肾功能不全（ＣＲＦ）患者血浆同型半胱氨酸（ＨＣＹ）浓度与健康人的差异,以及ＣＲＦ患者不同阶段ＨＣＹ浓度与肌酐水平的关系。方法：采用荧光偏振免疫法（ＦＰＩＡ）,对９９例ＣＲＦ患者和４５名健康志愿者进行血浆ＨＣＹ浓度测定。结果：不同阶段的 ＣＲＦ患者的ＨＣＹ水平均高于健康人组,且具有高度统计学差异（Ｐ＜０．０１）;ＣＲＦ患者 ＨＣＹ浓度随着肌酐水平的升高而升高。结论：临床应监测ＣＲＦ患者的ＨＣＹ血浆浓度,并对高ＨＣＹ血症患者给予相应的治疗,以减少闭塞性血管病变率．