Alfentanil kinetics in renal insufficiency

Summary Alfentanil 100 µg/kg was administered as an i.v. bolus to 9 patients with severe chronic renal dysfunction (creatinine clearance 1.0±1.2 ml/min) requiring regular haemodialysis. Plasma alfentanil concentrations were measured by a specific radioimmunoassay. Individual plasma concentration-time curves were fitted to a two-compartment open model. Mean distribution and elimination half-lives were 3.7 min and 58 min, respectively. The apparent volumes of distribution of the central compartment and the total volume of distribution at steady-state were 91 ml/kg and 304 ml/kg, respectively. Alfentanil plasma clearance was 5.3±2.5 ml/min/kg. All the patients tolerated alfentanil well and no side-effects nor delayed recovery were observed.     

Alprazolam kinetics in patients with renal insufficiency

Alprazolam kinetics following a single 1.0-mg oral dose of alprazolam were compared between seven dialysis-dependent patients with chronic renal failure and seven healthy controls matched for age, sex, and weight. There were no significant differences between patients and controls in alprazolam half-life (11.5 vs. 11.3 hours) or clearance of total drug (1.14 vs. 1.26 ml/min/kg). However, alprazolam free fraction was increased in renal failure patients (35.7% vs. 31.9% unbound, p less than 0.005). Free clearance of alprazolam averaged 23% lower in patients (3.2 vs. 4.1 ml/min/kg), but the difference was not significant. Renal insufficiency has a quantitatively small influence on alprazolam pharmacokinetics.     

Nalidixic acid kinetics in renal insufficiency.

1 A pharmacokinetic study of nalidixic acid (NA) and metabolites was carried out in 23 patients with differing renal function so as to determine the influence of renal insufficiency on the excretion and biotransformation rate of this antibacterial agent. Plasma and urine concentration of NA and of its 7-hydroxy (HNA) and 7-carboxy (CNA) derivatives were measured after a single oral administration. 2 Renal insufficiency did not markedly affect the renal clearance of NA while it significantly decreased the elimination rate of HNA, a compound which largely excreted into the urine. 3 Interestingly, CNA which could never be detected in the plasma of patients with normal renal function appeared in that of patients with renal insufficiency. Plasma concentrations of CNA and creatinine were positively related, and the amount of urinary CNA increased with the renal impairment. 4 These results suggest that HNA can still be biotransformed into CNA by the impaired kidney. Since CNA cannot be easily excreted in the urine of patients with renal insufficiency it is hypothesized that this compound back diffuses into the plasma. 5 Finally, the study of the urinary concentrations of NA and metabolites shows that a standard NA dosage can be used, at least in patients with mild renal insufficiency.     

Biotransformation of diflunisal and renal excretion of its glucuronides in renal insufficiency

1 A single oral dose of 500 mg diflunisal was administered to control subjects and patients with varying degrees of renal insufficiency to estimate the disposition kinetics of this drug.

2 Diflunisal and the sum of its ester and ether glucuronides conjugates were measured fluorimetrically.

3 In normals terminal plasma half-lives (T_½β) of diflunisal and its glucuronides were very similar: 10.8 h and 11.8 h respectively. The finding that plasma half-life was shortened with declining diflunisal plasma levels suggests capacity-limited elimination.

4 In subjects with normal renal function 78.6 ± 2.7% of the administered dose was recovered in 72 h urine, mainly as the glucuronide conjugates.

5 With increasing degree of renal function impairment T_½β of diflunisal was progressively prolonged up to ten times normal probably due to slowed biotransformation. This was associated with increasing retention of the conjugated metabolites in plasma due to marked reduction of the urinary excretion of the glucuronide conjugates.

6 The apparent volume of distribution of diflunisal was very small in normals (7.3 ± 0.4 l) and was significantly increased in patients with renal insufficiency (up to 16.2 ± 2.2 l).

7 Diflunisal elimination studies performed during haemodialysis did not reveal any significant change in diflunisal plasma half-time. In vivo ultrafiltration studies during haemodialysis have shown that diflunisal is 98-99% plasma protein bound in uraemic patients.

8 The present study indicates that although diflunisal is primarily eliminated by biotransformation, T_½β is prolonged in renal insufficiency and dose adjustment will accordingly be required in patients with renal function impairment.

     

Disposition kinetics of disopyramide in patients with renal insufficiency

The pharmacokinetics of an intravenous injection of disopyramide was studied in five normal subjects and six patients with varying degrees of renal impairment. The elimination rate constant (β) was related to the endogenous creatinine clearance (Cl_cr). However, a decrease in β was not observed until the Cl_cr was reduced below 40 ml min^?1. Below 40 ml min^?1 a linear relationship existed between β and Cl_cr. Similarly, the plasma elimination half-life (t_½β) showed a significant increase when the Cl_cr was less than 30 ml min^?1. Hence, dosage modification for disopyramide is necessary only when renal function is severely impaired. Overall, the apparent volume of distribution in patients with renal insufficiency was reduced to two-thirds of that in normal subjects. Therefore, in patients with Cl_cr less than 40 ml min^?1 both the loading and maintenance dose of disopyramide should be reduced.     

Diazepam kinetics in patients with renal insufficiency or hyperthyroidism.

1 Eight patients with end-stage renal insufficiency on maintenance haemodialysis, and seven patients with newly diagnosed hyperthyroidism, received a single intravenous dose of diazepam, followed by blood sampling over the next 7 days. Fifteen healthy volunteer controls, matched with patients for age and sex, were similarly studied. 2 Diazepam half-life in renal failure patients (mean 37 h) was greatly reduced compared to controls (mean 92 h, P less than 0.05) and clearance of total (free plus bound) diazepam correspondingly increased (0.94 v 0.34 ml min-1 kg-1, P less than 0.01). 3 However, differences were largely related to disease-related changes in drug binding and distribution. Mean unbound fraction of diazepam in plasma of renal patients (7.0%) was greatly increased over controls (1.4%, P less than 0.01) and Vd of unbound diazepam greatly reduced (57 v 157 l/kg, P less than 0.01). 4 Clearance of pharmacologically active unbound diazepam (intrinsic clearance) was not significantly different between renal patients and controls (23 vs 30 ml min-1 kg-1). 5 None of the kinetic variables for total or unbound diazepam in thyrotoxic patients differed significantly from those in controls matched for age and sex. 6 End-stage renal failure (or its associated drug therapy) alters diazepam protein binding and distribution, but does not significantly change clearance of unbound drug. Thyrotoxicosis does not influence diazepam kinetics.     

Influence of renal insufficiency on the pharmacokinetics of cicletanine and its effects on the urinary excretion of electrolytes and prostanoids.

1. The kinetics of a single oral dose (300 mg) of cicletanine a new antihypertensive drug with diuretic properties, and its effects on the urinary excretion of electrolytes and of the major stable metabolites of prostacyclin and thromboxane A2 were studied in patients with normal renal function (n = 6), mild (n = 9) and severe (n = 10) renal insufficiency. 2. In normotensive subjects with normal renal function, cicletanine was rapidly and regularly absorbed, its apparent elimination half-life established around 7 h, and both its renal clearance (0.4 ml min-1) and its cumulative renal excretion (0.85% of the administered dose), were low. Mild renal insufficiency did not significantly alter these parameters, while severe renal impairment reduced the renal clearance and the cumulative urinary excretion of cicletanine and increased its apparent elimination half-life (31 h). However the area under the plasma curve was not changed due to reduced plasma concentrations in these patients. 3. Cicletanine induced a rapid and marked (four fold as a mean) increase in the urinary excretion of water, sodium and potassium which lasted for 6 to 10 h, in subjects with normal renal function. Renal insufficiency did not alter the slope of the calculated plasma concentration-effects curves but reduced the maximum effect observed for water, sodium and potassium. 4. A single oral dose of cicletanine did not change the urinary excretion of 6-keto-prostaglandin F1 alpha and thromboxane B2 in the three groups of patients studied, the basal values of which being found to be closely related to the creatinine clearance.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lead exposure and renal failure: Does renal insufficiency influence lead kinetics?

Blood and urine lead concentrations have been measured in 40 subjects with normal and impaired renal function. Derived renal lead clearance varied widely, but was not influenced by the degree of renal impairment. Lead, however, appeared to reduce its own clearance. These findings provide additional evidence of nephrotoxicity from sub-clinical lead exposure.     

The effect of famotidine on renal function in patients with renal insufficiency.

The effect of famotidine, a new histamine H2-receptor antagonist, on renal tubular creatinine secretion was evaluated in twelve patients with reduced renal function (creatinine clearance 10-60 ml min-1). Creatinine and inulin clearances were determined at baseline and for 4 h after a 10 mg intravenous dose of famotidine. Famotidine renal clearance exceeded inulin clearance by an average of 152%, indicating that renal tubular secretion of famotidine occurred. No significant changes in the clearances of creatinine or inulin, or the fractional clearance of creatinine were observed after famotidine administration. These data suggest that famotidine, unlike cimetidine, does not inhibit renal tubular secretion of creatinine. Thus, famotidine does not affect creatinine-dependent measurements of renal function and is unlikely to alter the renal elimination of basic drugs.     

Effects of flurbiprofen on renal function in patients with moderate renal insufficiency.

1. Renal function was assessed in eight patients with chronic renal insufficiency following the administration of flurbiprofen 50 mg as a single dose and after chronic administration of 50 mg four times daily for 8 and 27 days. Diet and fluid intake were controlled. 2. Inulin and creatinine clearances and urinary excretion of sodium were measured at baseline and every 20 min for at least 3 h after dosing. The time of the mean peak concentration of (S)-flurbiprofen was used to guide the analysis of the clearances. Creatinine clearance, urinary excretion of sodium, and serum sodium and potassium were also assessed for 24 h after the dose and on a daily basis. Body weight and blood pressure were measured on a daily basis. 3. Decrements in inulin and creatinine clearances were small and reversible within 3 h of an oral dose of flurbiprofen. Comparison of baseline clearances for the three study periods (first dose and at 8 and 27 days of chronic dosing) revealed a lack of chronic effect on glomerular filtration rate. 4. In contrast, flurbiprofen caused a substantial (73 to 86%) and progressive decrease in the urinary excretion of sodium that reached a nadir within 4-5 h after drug administration. However, comparison of baseline values did not differ, indicating that balance conditions had been re-established. 5. Results of 24 h assessments were in agreement with the clearance study results. Reduced urinary excretion of sodium appeared to be limited to the first few days of flurbiprofen administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

The influence of renal insufficiency and haemodialysis on the kinetics of ciprofibrate.

1. The kinetics of the hypolipidaemic drug, ciprofibrate, were studied after a single oral dose (100 mg) in subjects with normal renal function (n = 6), patients with mild (n = 6) and severe (n = 6) renal insufficiency as well as in haemodialysed patients (n = 5). 2. Under fasting conditions, ciprofibrate, was absorbed rapidly in subjects with normal renal function, and its apparent elimination half-life was approximately 81 h. Both renal clearance (0.15 ml min-1) and cumulative renal excretion (less than 7% of the administered dose) were low. 3. Mild renal insufficiency did not alter the pharmacokinetics of ciprofibrate, but severe renal impairment significantly reduced both its renal clearance and cumulative urinary excretion and increased the apparent elimination half-life. 4. A 5 h haemodialysis session did not lower the plasma concentrations of ciprofibrate. 5. It is concluded that, from a pharmacokinetic point of view, a reduction in the dosage of ciprofibrate should be considered in patients with a glomerular filtration rate below 30 ml min-1/1.73 m2.     

Captopril reduces renal excretion of prostaglandin E2 in the sodium-depleted rabbit

The effects of captopril on renal function and prostaglandin E2 excretion were investigated in rabbits undergoing chronic sodium depletion. Captopril administered for six days, via rate-controlled osmotic pumps, caused diuresis and marked natriuresis which were accompanied by a significant reduction of urinary prostaglandin E2 excretion and of glomerular filtration rate. It is concluded that captopril reduces the renal excretion of prostaglandin E2 and that its diuretic and natriuretic effects are prostaglandin E2-independent.     

The effect of nifedipine GITS on renal function in hypertensive patients with renal insufficiency

Twelve hypertensive patients with moderately severe renal dysfunction were entered into a protocol to assess the blood pressure and renal effects of the sustained release calcium antagonist, nifedipine GITS (30-180 mg/d given once a day) administered for 5 weeks. Nifedipine GITS monotherapy effectively lowered blood pressure in 50% of the patients. Glomerular filtration rate and effective renal plasma flow were increased 18% and 20%, respectively. The filtration fraction and urinary protein excretion remained unchanged. Changes that were observed in renal function were independent of the blood pressure responses of the patients; there was no correlation between the systemic and renal effect of nifedipine GITS monotherapy. Patients who had a poor systemic blood pressure response exhibited an increase in glomerular filtration rate (+11%) but had a decrease in effective renal plasma flow (-6%); patients who achieved a goal blood pressure response showed increases in both glomerular filtration rate (+35%) and effective renal plasma flow (+40%). These results show that nifedipine GITS monotherapy has the potential to improve renal function abnormalities that are encountered in hypertensive patients with renal disease; the improvement in renal function may be independent of their effect on systemic blood pressure.     

肾动脉支架术对轻中度肾功能不全合并肾动脉狭窄患者肾功能的影响

目的研究肾动脉支架术对轻中度肾功能不全合并肾动脉狭窄患者肾功能的影响。方法选取2015年1月~2016年1月在我院已经进行过肾动脉支架手术的轻中度肾功能不全合并肾动脉狭窄的280例患者,在手术前和手术后分别对这280例患者进行血压测试、血肌酐(Scr)以及肾小球滤过率等指标进行为期1年的跟踪观察记录,分别记录患者手术前、手术后3个月、手术后6个月以及手术后1年三种不同指标的值,并对三种指标进行统计分析和检验。结果经过肾动脉支架手术后,轻中度肾功能不全合并肾动脉狭窄患者的肾功能有了明显改善,血压值恢复正常率显著高于肾动脉支架手术前,血肌酐值与手术前差异有统计学意义,肾小球滤过率也比手术前有很大的改善,这三组指标较手术前差异有统计学意义(P0.05)。结论肾动脉支架术能够有效的治疗轻中度肾功能不全合并肾动脉狭窄疾病且有显著疗效,能够使患者重新恢复到健康,在临床治疗中值得推广和应用。     

Acute effects of clometacin on renal prostaglandin biosynthesis in healthy subjects

Summary In 6 healthy subjects the effect of clometacin on renal function, sodium and water excretion, plasma renin activity and urinary excretion of prostaglandins has been studied. After four days of treatment with clometacin, the excretion of urinary prostaglandins E₂, F₂ and 6 keto F₁ and thromboxane B₂ were reduced by 61.2, 41.2, 59 and 42%, respectively. 62% reduction in plasma renin activity was also observed. There was no significant change in mean blood pressure, heart rate, body weight, creatinine clearance or urinary excretion of sodium. It is concluded that clometacin is an efficient cyclooxygenase inhibitor in healthy individuals with a normal sodium intake, and that caution is required when giving clometacin to patients at risk of developing renal failure during treatment with a cyclooxygenase inhibitor.     

Dose- and time-dependent kinetics of the renal excretion of nitrofurantoin in the rabbit

A pharmacokinetic study on the renal excretion of nitrofurantoin was carried out in rabbits at doses ranging from 0.5 to 15 mg/kg. With increasing dose, nonlinear kinetics were observed in the tubular secretion, which appeared to show dose and time dependence. The disposition of nitrofurantoin after intravenous injection is well described by a one-compartment model with simultaneous first-order nonrenal elimination and renal elimination, which consists of glomerular filtration, active tubular secretion conforming to the Michaelis-Menten equation, and reabsorption clearance by nonionic diffusion. Plasma and urinary excretion data after intravenous injection of nitrofurantoin were fitted to this model. When the Michaelis constant was loosely restricted at a constant value, the maximum velocity decreased with increasing dose of nitrofurantoin. However, the Michaelis constant apparently increased with increasing dose when the maximum velocity was loosely restricted at a constant value. Although the results of this fitting suggested that the former case may occur in the active tubular secretory system, the latter case could not be completely eliminated because of limited data. The implications of these results are discussed on the basis of the available published data.     

Long-term clinical effects, bioavailability, and kinetics of minoxidil in relation to renal function.

Minoxidil was used to treat 26 patients (17 to 67 years old) with severe hypertension and varying degrees of renal function. Our object was to assess long-term clinical efficacy, kinetics (acute and chronic), and bioavailability of minoxidil in chronic renal insufficiency. Minoxidil, 27 to 30 mg per day, decreased systolic and diastolic blood pressure during the first three months of therapy. Between the third and 24th months (30 months in one patient) there was no further change. Propranolol or clonidine was needed to control heart rate, and furosemide or dialysis was needed to control edema induced by minoxidil. Renal function improved in some of the mildy azotemic patients. Minoxidil kinetics after the customary dose did not differ whether the drug was taken as tablet or solution. Kinetic parameters during chronic administration of minoxidil did not differ from those after acute administration. The kinetics in chronic renal insufficiency do not differ from these in subjects with normal renal function.     

肾衰康口服液对慢性肾衰大鼠肾功能及血脂代谢的影响

目的观察肾衰康口服液对慢性肾衰(chronic renal failure,CRF)大鼠肾功能、血脂和肾脏病理的影响。方法采用单侧肾脏摘除合并两次注射阿霉素法建立大鼠慢性肾衰模型,随机分为正常对照组、模型组、尿毒清阳性对照组、肾衰康口服液组(21、10.5、5.25 g·kg-1),90 d后采血检测血肌酐(creatinine,Cr)、尿素氮(blood urea nitrogen,BUN)、总蛋白(total protein,TP)、白蛋白(albumin,ALB)、总胆固醇(total cholesterol,TC)、甘油三酯(triglyceride,TG),肾脏标本用体积分数为10%的中性福尔马林固定,常规石蜡包埋,切片,HE染色,光镜观察。结果各给药组与模型组相比明显降低Cr、BUN、TC、TG,升高TP、ALB,作用呈剂量依赖性,高剂量组作用最好。结论肾衰康口服液有改善肾功能,调节脂质代谢紊乱的作用。