Pharmacokinetics of torasemide and its metabolites in end-stage renal disease

The pharmacokinetics of torasemide, a new loop diuretic, as well as its active metabolites M1 and M3, and its inactive main metabolite, M5, were studied in 12 patients with end-stage renal failure during single i.v. (n=6) or single oral (n=6) dosing of 200 mg torasemide, and during chronic oral treatment for 9 days (n=12).The elimination half-life (t_1/2) of torasemide was unchanged in renal failure, whereas t_1/2 of the torasemide metabolites M1, M3, and M5 were markedly prolonged. However t_1/2 as well as the area under the plasma level time curve of torasemide and its metabolites were unchanged during chronic compared to acute administration.The results of this study suggest that despite the increased half-life of torasemide metabolites M1, M3 and M5 in end-stage renal failure patients, no accumulation of the parent drug torasemide and its metabolites during chronic dosing is demonstrable.     

托拉塞米片的正常人体药动学研究

目的:研究健康国人单次口服托拉塞米片的体内药动学特点.方法:9例男性健康受试者以三周期、三交叉的拉丁方设计,分别口服托拉塞米5,10和20mg.采用高效液相色谱紫外检测法测定血浆中的托拉塞米浓度.结果:托拉塞米口服后吸收迅速,3个剂量组的达峰时间(Tmax)均在服药后1h左右,表观分布容积(Vd)约为17L.3个剂量组达峰浓度(Cmax)之比为1:2.3:4.6,药时曲线下面积(AUC0～14)之比为1:2.0:4.5;AUC0～∞之比为1:2.0:4.4,r=0.999.5,10和20mg消除半衰期t1/2( ke)分别为(3.77±1.25),(3.60±0.68)和(3.74±0.70)h;清除率(Cl)分别为(56.4±14.8),(56.3±10.3)和(51.6±12.8)mL·min-1,3个剂量组之间差异均无显著性.结论:健康国人单次口服托拉塞米的药动学呈线性动力学,Tmax为1h,t1/2约3.7h,Vd约为17L.     

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.     

呋塞米与托拉塞米间隔使用治疗慢性心力衰竭的临床观察

目的探讨呋塞米与托拉塞米间隔使用治疗慢性心力衰竭（CHF）的疗效。方法将符合纳入标准患者随机分成试验组和对照组。试验组先使用呋塞米片7 d,然后改为托拉塞米片7 d;对照组使用呋塞米片14 d。比较两组治疗14 d后总有效率、尿量、电解质及pro-BNP的差别。结果①试验组总有效率为89.66%,显著高于对照组（77.01%）,差异有统计学意义（χ^2=7.968,P=0.019）;②两组治疗后尿量较治疗前显著增加,差异有统计学意义（P〈0.05）,血钾和pro-BNP均较治疗前显著下降,差异有统计学意义（P〈0.05）;③治疗后试验组尿量和血钾显著高于对照组,差异有统计学意义（P〈0.05）,pro-BNP显著低于对照组,差异有统计学意义（P〈0.05）;④试验组总不良反应发生率及低钾血症发生率显著低于对照组,差异有统计学意义（P〈0.05）。结论呋塞米与托拉塞米间隔使用可提高CHF治疗的总有效率,增加尿量,减少电解质紊乱等不良反应。     

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.     

Saluretic effect of the loop diuretic torasemide in chronic renal failure

Summary The effects of torasemide have been studied in 7 healthy controls and 9 patients with stable chronic renal failure of various degrees.After a control period of 3 days torasemide 20 mg i. v. caused a dramatic increase in diuresis and electrolyte excretion without affecting the glomerular filtration rate. The duration of action of torasemide, , averaged 6 h and was independent of the creatinine clearance, CL_CR. When related to the drug-induced excretion of Cl^–, Na⁺, K⁺, Ca²⁺ and Mg²⁺ showed strong linear dependence on CL_CR. Both the kaliuresis and the calciuresis during were tightly correlated with the natriuresis over the broad range of CL_CR. Similarly, the excretion of Mg²⁺ was dependent on the kaliuresis.The torasemide-induced kaliuresis amounted to 12% of natriuresis, as after furosemide. The kaliuretic effect of loop diuretics is smaller than that of the thiazides. After , e. g. over a 24 h period, kaliuresis was not correlated with natriuresis. The magnitude of the rebound effect was diminished with increasing renal impairment.In memory of our colleague and friend U. Wais who left us too early     

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 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.     

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.     

托拉塞米胶囊与片剂在健康人体内的药动学和生物等效性

目的研究托拉塞米试验制剂(胶囊)和参比制剂(片剂)的人体药动学和生物等效性.方法20名健康受试者随机交叉口服托拉塞米胶囊(试验制剂)和托拉塞米片(参比制剂),剂量均为10 mg.血样加入内标(呋塞米)经预处理后采用HPLC法测定.结果试验胶囊、参比片剂的主要药动学参数Cmax分别为(1160.1±188.0),(1 271.2±326.8)μg·L-1;Tmax分别为(1.1±0.4),(1.0±0.4)h;t1/2分别为(4.1±1.0),(4.0±1.0)h;AUC0-t分别为(3 662.3±782.2),(3 783.2±1390.1)μg·h·L-1.以AUC0→t计算的试验胶囊的相对生物利用度为(100.6±23.9)%.结论经方差分析及双单侧t检验结果显示,试验制剂和参比制剂具有生物等效性.     

托拉塞米联合美托洛尔治疗慢性充血性心力衰竭的临床研究

目的 探讨托拉塞米联合美托洛尔治疗慢性充血性心力衰竭的临床疗效。方法 选取2017年1月－2018年12月在延安大学附属医院接受住院治疗的116例慢性充血性心力衰竭患者为研究对象。对照组患者口服酒石酸美托洛尔片,起初6.25 mg/次,2~3次/d,以后视临床情况每数日至1周增加6.25~12.5 mg,2~3次/d,最大剂量可用至50~100 mg/次,2次/d;观察组在对照组基础上加用托拉塞米片,起初剂量为10 mg/次,1次/d,以后视临床情况可将剂量增至20 mg/次,1次/d,最大剂量可用至每日40 mg。两组患者均连续治疗7 d。观察两组患者的临床疗效,同时比较两组患者治疗前后的二尖瓣舒张早期与舒张晚期血流峰值速度比值（E/A）、左室射血分数（LVEF）、左心室舒张末期内径（LVEDD）、左室收缩末期内径（LVESD）、血钠、血钾、血肌酐（Scr）、血清嗜铬粒蛋白A（CgA）及半乳糖凝集素-3（galectin-3）水平。结果 治疗后,观察组患者总有效率为87.9%,明显高于对照组的70.7%（P<0.05）。治疗后,两组患者LVEDD、LVESD均显著降低（P<0.05）,与对照组比较,观察组下降程度更明显（P<0.05）;两组患者E/A、LVEF均显著上升（P<0.05）,与对照组比较,观察组上升程度更明显（P<0.05）。治疗后,两组24 h尿量显著增多（P<0.05）,并且观察组24 h尿量显著多于对照组（P<0.05）;治疗后,两组患者血钠、血钾、Scr的比较差异均无统计学意义。治疗后,两组患者血清CgA及galectin-3水平显著降低（P<0.05）,且观察组明显低于对照组（P<0.05）。结论 托拉塞米联合美托洛尔治疗慢性充血性心力衰竭疗效较好,有利于缓解临床症状,改善心功能,降低血清CgA和galectin-3的水平,抑制心肌纤维化进程,明显改善心室重构,提高治疗效果。     

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.     

Paracetamol disposition and metabolite kinetics in patients with chronic renal failure

Summary The disposition of paracetamol following an oral dose of 1.0 g was compared in 10 healthy volunteers, 7 patients with moderate chronic renal failure and 6 patients with end stage renal failure on maintenance haemodialysis.Paracetamol absorption was normal in the patients with renal failure. The mean plasma half-life of paracetamol from 2 to 8 h was similar in the 3 groups (2.1 to 2.3 h) but from 8 to 24 h it disappeared much more slowly in the renal failure patients (half-life 11.7 compared with 4.9 h in the healthy volunteers). Plasma concentrations of paracetamol glucuronide and sulphate conjugates were greatly increased in the patients with moderate renal failure and the mean plasma half-lives were 30.5 and 21.8 h respectively compared with about 3 h in the healthy volunteers. Plasma concentrations of these metabolites were even higher in the dialysis patients and there was no significant fall over 24 h. The cysteine and mercapturic acid conjugates of paracetamol could only be measured in plasma in the patients with renal failure and concentrations were very low.The fractional urinary recovery of paracetamol and its glucuronide, sulphate, cysteine and mercapturic acid conjugates was similar in healthy volunteers and patients with moderate renal failure. The mean renal clearances of paracetamol and its glucuronide and sulphate conjugates in the healthy volunteers and patients with moderate renal failure were 15.7, 137 and 172, and 5.9, 14.5 and 14.8 ml/min respectively. In the latter patients the mean renal clearances of the cysteine and mercapturic acid conjugates were much greater at 35.4 and 80.2 ml/min. In the patients with moderate renal failure the AUC's of the glucuronide and sulphate conjugates were related to the plasma creatinine and there were significant negative correlations with the renal clearances of these metabolites and total urinary recovery. Marked cumulation of the polar glucuronide and sulphate conjugates of paracetamol would seem inevitable in patients with renal failure and the parent drug is apparently regenerated to a limited extent from retained metabolites.     

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.     

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 lansoprazole in patients with renal or liver disease of varying severity

Summary The pharmacokinetics of lansoprazole (L) after a single oral dose of 30 mg was determined in 18 healthy volunteers, 17 renal failure patients and 24 hepatic failure patients; 8 hepatitis and 16 with compensated (CC) or uncompensated (UCC) cirrhosis.In renal failure, the absorption of L was unchanged, its half-life being similar to that in healthy subjects; a small change seen in mild renal failure patients (creatinine clearance between 40 and 60 ml/min) was attributed to the age of the patients. Urinary elimination, essentially as metabolites of lansoprazole, was decreased, in relation to the degree of renal impairment.In hepatitis patients, the AUC and t_1/2 of L were doubled, without any change in C_max. In cirrhotics t_max was prolonged, the AUC was increased (P<0.001) and there was prolongation of t_1/2 (6.1 h in CC and 7.2 h in UCC compared to 1.4 h in healthy subjects). These changes resulted from a decrease in the clearance of L. There was also an increase in its sulphone metabolite (C_max, R_m) and a decrease in the hydroxylated metabolite (C_max, R_m) in relation to the degree of liver disease, and reflecting a decrease in hydroxylation and biliary elimination.Thus, renal failure had no effect on the pharmacokinetics of L, but severe hepatic failure caused marked changes. A repeated dosing study would be necessary to evaluate the repercussions of the possible accumulation in cirrhotic patients.     

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.     

Pharmacokinetics of penbutolol and its metabolites in renal insufficiency

Summary The pharmacokinetics of penbutolol, its 4-hydroxylated metabolite and of their conjugates was studied in hypertensive patients with various degrees of renal impairment.A single oral dose of penbutolol 40 mg, was rapidly absorbed after a lag-time of 0.34 h. Its plasma concentration reached a maximum after 0.84 h and then declined bi-exponentially, with an apparent elimination half-life of 21.8 h. The hydroxylation of penbutolol was negligible and conjugation was of major importance for its elimination. Consequently, the kinetics of unchanged penbutolol were not altered by renal impairment. The 48 h-urinary excretion of penbutolol and its metabolites reached 13–14% of the administered dose, which is consistent with extensive metabolism of the drug.After treatment for 30 days with penbutolol 40 mg/d there was no accumulation of the parent drug but the concentration of its conjugates was increased.It is concluded that the dose of penbutolol need not be changed in patients with mild renal insufficiency, 4-hydroxypenbutolol is unlikely to participate in the anti-hypertensive effect of the drug, due to its low concentrations, and biotransformation of penbutolol may be enhanced during chronic treatment.     

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.