The pharmacokinetics of enalapril in hospitalized patients with congestive heart failure.

The pharmacokinetics of the converting enzyme inhibitor, enalapril, were studied in an open, randomized, balanced crossover design in 12 hospitalized patients with stable, chronic congestive heart failure (CHF). Enalapril maleate is a prodrug requiring in vivo hepatic esterolysis to yield the active diacid inhibitor enalaprilat. CHF results in changes in regional blood flow that may affect the gastrointestinal absorption, hepatic hydrolysis and renal excretion of enalapril and enalaprilat. In order to evaluate the pharmacokinetics of enalapril in CHF, the following treatments were given: enalapril maleate 10 mg orally, enalapril maleate 5 mg intravenously and enalaprilat 5 mg intravenously. Each dose was followed by a 72 h period with frequent blood sampling and fractionated urine collection for the radioimmunoassay of enalaprilat, before and after sample hydrolysis. Mean absorption for the oral dose was 69%, hydrolysis 55%, bioavailability 38%, urinary recovery 77% and estimated first-pass effect 10%. The results were compared with available data in normal subjects. After oral administration of 10 mg enalapril maleate, the extent of absorption, the degree of hydrolysis and the bioavailability in CHF patients appear to be similar to those in normals with differences less than 10%. The rate of absorption and hydrolysis appear to be slightly slower in CHF. The serum concentrations of enalaprilat were consistently greater in CHF and maximal concentrations were reached at 6 h in CHF as compared to 4 h in normal subjects. We conclude that the presence of CHF does not appreciably alter the pharmacokinetic behaviour of enalapril. The observed differences may be associated with age as well as the disease state.     

The influence of hydrochlorothiazide on the pharmacokinetics of enalapril in elderly patients

In a randomized, cross-over, single-dose study of 19 elderly hypertensive patients (aged 62-84 y, SBP greater than 160 mmHg, DBP greater than 100 mmHg, creatinine clearance 11-93 ml.min-1) we have studied the pharmacokinetics of the angiotensin converting enzyme (ACE) inhibitor enalapril after a single oral dose of either 10 mg enalapril or 10 mg enalapril + 25 mg hydrochlorothiazide. The pharmacokinetics of enalapril were unaffected by hydrochlorothiazide, but there was a significant reduction in renal clearance and a significant increase in AUC(0-24 h) of enalaprilat after hydrochlorothiazide, resulting in higher serum concentrations of the active drug. This was independent of the individual degree of renal impairment and might be due either to an initial reduction of GFR by hydrochlorothiazide or to interference with the tubular secretion of enalaprilat. The relationships between serum enalaprilat and serum ACE activity were similar after both treatments, both consistent with a value for Ki of enalaprilat of about 0.1 nmol.l-1. Thus, serum ACE activity was not affected by hydrochlorothiazide but completely reflected the pharmacokinetics of enalaprilat in both treatments.     

Comparison of the pharmacokinetics of fosinoprilat with enalaprilat and lisinopril in patients with congestive heart failure and chronic renal insufficiency

AIMS: To compare the serum pharmacokinetics of fosinoprilat with enalaprilat and lisinopril after 1 and 10 days of dosing with fosinopril, enalapril and lisinopril. METHODS: Patients with congestive heart failure (CHF, NYHA Class II-IV) and chronic renal insufficiency (creatinine clearance 相似文献   

Influence of food on the bioavailability of enalapril

In a randomized, two-period crossover study in 12 normal volunteers, serum and urine concentrations of the angiotensin-converting enzyme inhibitor enalapril and its active metabolite enalaprilat were determined following administration of a single 40-mg tablet of enalapril maleate administered both in the fasting state and with a standard breakfast. A 7-d interval separated the two treatment periods. Area under the serum concentration-time curves for enalaprilat and urinary recoveries for enalaprilat and total drug did not differ significantly between the fed and fasted conditions. The mean observed maximum serum concentration of enalaprilat was slightly higher for the fasting treatment, but the time to peak concentration was almost identical for the two treatments. Enalapril maleate is unlike the prototype angiotensin-converting enzyme inhibitor captopril in that a standard meal does not appear to influence absorption of this new drug.     

Pharmacokinetics and converting enzyme inhibition after morning and evening administration of oral enalapril to healthy subjects

Summary Possible circadian changes in the pharmacokinetics and effect on serum angiotensin-converting enzyme (ACE) activity of the ACE inhibitor enalapril have been studied in 8 healthy subjects after oral ingestion of 10 mg enalapril maleate either at 08.00 h or 20.00 h. The time to peak serum concentration (t_max) of enalapril was increased after administration at 20.00 h compared to 08.00 h (2.4 h versus 1.3 h), where as other kinetic parameters were not significantly altered. The 24 h-kinetics of the active metabolite enalaprilat did not differ significantly between the two treatments, but the area under the curve (AUC (0–24)) and the peak serum concentration (C_max) were slightly higher after intake at 20.00 h. The relationship between the measured serum enalaprilat level and the degree of inhibition of serum ACE was the same after both treatments. Overall, the evening and morning administration of enalapril did not differ markedly in the pharmacokinetics and the time course of ACE inhibition.This report is part of the thesis to be presented by K. Weisser in partial fulfillment of the requirements for the degree of Doctor of Natural Science.     

Comparison of the steady-state pharmacokinetics of fosinopril, lisinopril and enalapril in patients with chronic renal insufficiency.

The phosphinyl ester prodrug fosinopril, a new angiotensin converting enzyme (ACE) inhibitor, is fully hydrolysed after oral administration to the pharmacologically active diacid, fosinoprilat. This metabolite is cleared by both hepatic and renal routes, while most other ACE inhibitors are cleared exclusively by the kidney. In the present study, after administration of multiple fixed oral doses the accumulation of the active moieties of fosinopril, enalapril and lisinopril was compared in patients with renal insufficiency. 29 patients with creatinine clearances (CLCR) less than 30 ml/min received either fosinopril 10mg (n = 9), enalapril 2.5mg (n = 10) or lisinopril 5mg (n = 10) once daily for 10 days in a nonblind (open-label) parallel study. Pharmacokinetic parameters including area under the serum concentration-time curve (AUC), peak serum concentration (Cmax) and time to peak concentration (tmax), as well as renal function, blood pressure, and plasma renin activity (PRA) and aldosterone levels, were determined on the first and last days of the study. The percentage (+/- SEM) increases in AUC from day 1 to day 10 for fosinoprilat, enalaprilat and lisinopril were 26.8 +/- 9.9 (nonsignificant), 76.6 +/- 16.6 (p less than 0.001) and 161.7 +/- 31.8% (p less than 0.001), respectively. These results indicate that there was significantly less accumulation of fosinoprilat, based on accumulation indices, relative to either enalaprilat (p less than 0.05) or lisinopril (p less than 0.001) during the study. The Cmax of fosinopril increased significantly less than that of lisinopril (21.1 vs 123.6%; p less than 0.01). Renal function was not altered in any group, and blood pressure changed modestly.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of enalapril in normal subjects and patients with renal impairment.

The pharmacokinetics of enalaprilat were studied after administration of single and multiple doses of enalapril maleate to people with normal and impaired renal function. Renal impairment was associated with higher serum concentrations of enalaprilat, longer times to peak concentrations, slower decline of serum concentrations and with reduced urinary elimination. Urinary elimination of enalaprilat was closely related to renal function. In patients with severe renal impairment (GFR values below 30 ml min-1 1.73 m-2) significantly smaller doses of enalapril maleate will be required than in patients with normal or less severely impaired renal function.     

Effect of cimetidine on the pharmacokinetics and pharmacodynamics of enalapril in normal volunteers

The possible effects of cimetidine on the pharmacokinetics and pharmacodynamics of enalapril, a pro-drug requiring hepatic de-esterification to an active angiotensin-converting enzyme (ACE) inhibitor enalaprilat, were assessed in a randomized, crossover study. Cimetidine (400 mg) or placebo was administered orally every 12 h for 3 days and on the day of a single oral administration of enalapril maleate (10 mg) to seven healthy male subjects. Serum ACE, plasma renin activity (PRA), plasma aldosterone concentration (PAC), and alpha-human atrial natriuretic peptide (alpha-hANP) were measured before and 4 h after the enalapril dosing. There were no significant differences in any serum- and urine-derived kinetic parameters of enalapril and enalaprilat, nor in hemodynamics, PAC, or alpha-hANP between the two treatment trials. ACE decreased and PRA increased to a similar extent in the two trials. Serum enalaprilat concentration correlated significantly (p less than 0.001) with percentage of inhibition of ACE activity. The results suggest that the pharmacokinetics and pharmacodynamics of enalapril are unaffected by preadministration of cimetidine. Thus, cimetidine does not appear to alter hepatic esterase activity toward enalapril.     

Disposition of enalapril and its diacid metabolite, enalaprilat, in a perfused rat liver preparation. Presence of a diffusional barrier for enalaprilat into hepatocytes

Enalaprilat (MK-422), a new and potent angiotensin- converting enzyme inhibitor, and its monoethyl ester precursor, enalapril, were studied in a single pass perfused rat liver preparation under constant perfusate flow (10 ml/min) at concentrations of 0.29-0.41 microM for 14C-enalapril and 0.01-0.015 microM for 3H- enalaprilat . During their simultaneous delivery to the same rat liver preparation, the steady state hepatic extraction ratio of 14C-enalapril was high (0.861 +/- 0.02) and 14C- enalaprilat appeared rapidly in effluent perfusate plasma. Of the enalapril dose, 22.7 +/- 6.9% appeared in bile. 14C- Enalaprilat accounted for 79% of the total radioactivity in bile (18% of dose) whereas 14C-enalapril was present only as 10% of the total (2.3% of dose). By contrast, the steady state hepatic extraction of 3H- enalaprilat was very low (0.053) and the disappearance was virtually identical to the appearance of 3H- enalaprilat in bile. These findings suggest that diffusional barrier exists for enalaprilat as the preformed metabolite, which hinders penetration into hepatocytes, and therefore, elimination. The precursor, enalapril, effectively brings enalaprilat into hepatocytes were more extensive biliary excretion of the generated metabolite takes place. This account adds to our further understanding of metabolite kinetics; in addition to the uneven distribution of enzyme system and the intrinsic clearance for metabolite formation and elimination, the presence of a diffusional barrier is another important determinant which may cause deviations between the kinetics of a generated and performed metabolite.     

Bioequivalence study of two enalapril maleate tablet formulations in healthy male volunteers Pharmacokinetic versus pharmacodynamic approach

Objective: Two different conventional release enalapril maleate tablet formulations were evaluated for their relative bioavailability (Eupressin tablets 10 mg, Biosintética as the test formulation vs Renitec tablets 10 mg Merck Sharp & Dhome, as the reference formulation). A single 20 mg oral dose of each preparation was administered to 18 healthy male adult volunteers and their bioequivalence was assessed by comparing the serum enalaprilat and total enalapril (enalaprilat plus enalapril maleate) concentration-time curves. Angiotensin converting enzyme (ACE) activity was also quantified in each serum sample. Results: The pharmacokinetic parameters obtained for each formulation were the area under the time-concentration curve from 0 to 24 h (AUC_[0–24]), maximum concentration C_max and the time at which it occurred (t_max). When serum enalaprilat concentration-time curves were employed to assess bioequivalence, the formulations were bioequivalent in the extent but not in the rate of absorption. However, no difference in either the extent or the rate of absorption were observed when serum total enalapril vs time curves were analysed. ACE activity-time curves were similar for both formulations and showed that ACE was 90% inhibited 3–5 h after enalapril administration, and till approximately 50% after 24 h. At that time, circulating enalaprilat and total enalapril levels were less than the tenth of C_max. Conclusion: The results show that complete bioequivalence of the two formulations can be concluded from serum total enalapril concentration data, and that serum ACE activity is not a suitable pharmacodynamic variable for assessing bioequivalence. Received: 29 May 1995/Accepted in revised form: 30 October 1995     

Elevated plasma nilvadipine concentration after single and chronic oral administration to patients with chronic liver disease

Summary Fourteen normotensive patients with liver disease (6 with cirrhosis and 8 with chronic hepatitis) and 7 healthy volunteers were given a single oral dose of nilvadipine 2 mg. In addition, nilvadipine 4 mg was administered orally twice daily for several months to 6 hypertensive patients with mild liver dysfunction and 18 hypertensives with normal liver function.A significant increase in plasma nilvadipine was found in the patients with cirrhosis as compared both to the normal and chronic hepatitis subjects; the time to peak concentration was similar among the three groups.The peak plasma nilvadipine concentration was closely correlated both with the serum albumin level and the retention of indocyanine green. Changes in blood pressure, pulse rate and various vasoactive hormones following a single oral dose of nilvadipine did not differ between the groups.Thus, an increase in plasma nilvadipine relative to the level in normal subjects was demonstrated in patients with cirrhosis following a single oral dose, as well as in patients with slight liver dysfunction following long-term oral administration.     

Enalapril in RAPIDISC (wafer formulation): pharmacokinetic evaluation of a novel, convenient formulation

BACKGROUND: Enalapril in RAPIDISC* (wafer), a new easy-to-administer formulation of enalapril, may improve the convenience of enalapril therapy, thereby helping patients adhere to antihypertensive treatment. SUBJECTS AND METHODS: To determine whether 20 mg enalapril wafer is bioequivalent to the conventional 20 mg enalapril tablet, an open-label, two-period crossover study was performed in 16 healthy male volunteers. Cumulative urinary recovery of free enalaprilat (active metabolite of enalapril) and the serum maximum concentration of free enalaprilat (Cmax) were the primary pharmacokinetic parameters used to determine bioequivalence in this study. Bioequivalence was defined as the geometric mean ratio (wafer: tablet) falling within the equivalence limits of 0.80 to 1.25 for both parameters. RESULTS: Cumulative urinary recovery of free enalaprilat (0 - 72 hours) was similar between the wafer and conventional tablet formulations (arithmetic mean 5.13 vs. 5.03 mg, about 36% of dose). The geometric mean ratio of the urinary recovery of free enalaprilat (wafer: tablet) was 1.03 (90% CI: 0.93, 1.15). Cmax of serum enalaprilat was also similar between the wafer and conventional tablet formulations (arithmetic mean 85.7 vs. 76.3 ng/ml). The geometric mean Cmax ratio (wafer: tablet) was 1. 10 (90% CI: 1.00, 1.22). Both enalapril formulations were well tolerated. CONCLUSION: This study demonstrates that 20 mg enalapril in RAPIDISC is bioequivalent to 20 mg enalapril conventional tablet.     

Chronopharmacology of enalapril in hypertensive patients

The pharmacokinetics and pharmacodynamics of enalapril, an angiotensin converting enzyme inhibitor, are reported to vary with the time of administration. The present study was undertaken to examine whether the effect of enalapril on plasma bradykinin (BK), substance P and prostaglandin E₂ (PGE₂), which are likely to be involved in the mechanism of enalaprilinduced cough, might also be affected by its time of administration. Enalapril 5 mg or placebo was given orally at 10:00 h (day trial) or 22:00 h (night trial) to 12 patients with essential hypertension. Serum concentrations of total drug (enalapril + enalaprilat, its active metabolite) during the day and night trials did not differ significantly at any time. However, serum enalaprilat tended to be higher and its maximum concentration greater in the day trial than in the night trial. Blood pressure 24 h after administration of enalapril was reduced at 22:00 h, but not at 10:00 h. Plasma BK tended to increase following enalapril administration at 10:00 h, but not at 22:00 h. Remarkable increases in plasma BK were observed in two patients in the day trial and one of them also complained of cough. However, no such increase in plasma BK or subsequent adverse effect were recorded in the night trial. Plasma substance P and PGE₂ did not change significantly following enalapril administration either in the day or night trial. The results suggest that the response of BK to enalapril is affected by the time of administration. In patients who complain of cough during treatment with enalapril during the daytime, this adverse effect might be dminished or eliminated by a switch to night-time administration.     

A possible drug interaction between rifampicin and enalapril

Summary When a 35-year-old man with essential hypertension was treated with antibiotics for brucellosis his blood pressure rose significantly. While all other treatment was kept constant rifampicin was discontinued. On rechallenge rifampicin did not alter serum concentrations of enalapril or the area under the curve (AUC) between 0 and 7 h, but it did reduce the AUC of the active metabolite enalaprilat by 31%. These observations suggest that there may be an interaction between rifampicin and enalapril, causing reduced hypotensive efficacy of enalapril. The mechanism of such an interaction merits further study, but it could be due to enhanced renal clearance of enalaprilat.     

肝硬化和肝癌患者血清C-反应蛋白测定的临床价值

目的:探讨血清C-反应蛋白(CRP)的测定在肝硬化和肝癌中的临床应用价值.方法:采用散射比浊法测定52例肝硬化、30例肝癌以及30例正常对照者的血清CRP水平,同时采用放免法检测各组血清甲胎蛋白(AFP)含量,并与CRP结果进行对比分析.结果:各疾病组患者血清 CRP 水平明显高于正常对照组(P＜0.001,P＜0.05),而且肝癌组＞肝硬化组,肝硬化失代偿组＞肝硬化代偿组,差异越大,预后越差.单独检测血清CRP和AFP对肝癌诊断的灵敏度分别是86.7%和80.0%;特异性分别是65.8%和78.0%;以CRP和AFP至少1项阳性作为判断标准,灵敏度上升为96.7%.结论:检测肝硬化、肝癌患者血清CRP含量,有助于发现和了解肝内炎症活动及肝细胞受损的状况,为临床诊断和治疗提供重要的参考依据.单独检测血清CRP不是诊断肝癌的理想指标,但血清CRP和AFP的联合检测对肝癌诊断有互补作用.     

Pharmacokinetic assessment of an oral enalapril suspension for use in children

The angiotensin-converting enzyme (ACE) inhibitor enalapril is commonly used to treat pediatric hypertension. Because some children are unable to swallow tablets or require doses less than the lowest available enalapril tablet, an enalapril suspension was developed. This study examined the relative bioavailability of enalapril suspension (10 mg) (S) compared with 10-mg marketed VASOTEC tablets (T) in 16 healthy adult subjects. The geometric mean ratio (S/T) estimate of urinary recovery of free enalaprilat, the active moiety, was 0.92 (90% confidence interval (CI): 0.80, 1.07). Urinary recovery data indicate that approximately 50% of the dose was absorbed (50% recovered in urine as enalapril plus enalaprilat) with about 30% of the dose recovered as free enalaprilat for both S and T. The geometric mean ratios (S/T) of serum AUC and C(max) were 1.01 (90% CI: 0.90, 1.13) and 0.98 (90% CI: 0.83, 1.16), respectively. Suspension T(max) was slightly shorter (0.5 h) than that for tablet, but this difference is not clinically significant. Both formulations were well tolerated and there were no clinically significant adverse experiences. We conclude that the bioavailability of enalapril oral suspension 10-mg is similar to that of VASOTEC 10-mg tablet. Instructions for compounding enalapril are provided.     

Effect of diffusional barriers on drug and metabolite kinetics

Previous experimental and simulation studies have alluded to the presence of a diffusional barrier for enalaprilat, the polar, dicarboxylic acid metabolite of enalapril, entering hepatocytes. The present study examined the roles of diffusional clearances of drug and metabolite on the distribution and elimination characteristics in liver. The hepatic intrinsic clearances for enalapril (26.1 ml/min) and enalaprilat (0.7 ml/min), found in a previous study, were used for simulation because, along with their given diffusional clearances (75 and 2 ml/min, respectively), they yielded a high extraction ratio for drug (E = 0.86) and a poor extraction ratio for the preformed metabolite (E = 0.05). While maintaining the intrinsic clearances and hepatic blood flow rate (10 ml/min) constant, only drug and metabolite diffusional clearances were altered. The liver was modeled as three (blood, liver tissue, and bile) compartments, with blood flowing into sinusoids of uniform length L. Blood (sinusoidal) and tissue concentrations of drug and generated and preformed metabolites, at any point x along L and under linear kinetic conditions, were approximated numerically by computer simulations and expressed as the length-averaged or mean concentrations. The factors underlying drug and metabolite (preformed and generated) concentrations, hepatic clearances and elimination rates, and their interrelationships were illustrated graphically, emphasizing the roles of diffusional clearances for drug and metabolite on their spatial distributions and elimination in liver.     

Pharmacokinetics of repeated single oral doses of enalapril maleate (mk-421) in normal volunteers

Enalapril, the ethyl ester of a potent angiotensin converting enzyme inhibitor, enalaprilat, was administered to healthy volunteers as a capsule containing 10 mg of the maleate salt, every 24 h for eight doses. Serum profiles show little accumulation of enalaprilat following eight daily doses of enalapril maleate. An average effective half-life for accumulation of approximately 11 h was calculated from urine data. Comparison of observed 24-h urinary recoveries of enalaprilat to predicted steady-state recovery indicates that an ‘average’ steady state for enalaprilat is attained by the third or fourth dose of enalapril maleate. Statistical comparison of daily urinary recoveries, as well as C_min values for enalaprilat, confirm this. Observed fluctuations in serum and urine data during apparent steady state suggest some day-to-day variability in the absorption of enalapril maleate and/or its hydrolysis to enalaprilat. An accumulation ratio of 1·3 for enalaprilat was calculated from the predicted steady-state urinary recovery and observed urinary recovery for dose one.     

Clinical investigation of the biliary excretion of cefoperazone in obstructive jaundice

In the present study, we investigated the biliary excretion of cefoperazone (CPZ) in patients with complete obstruction in the lower bile duct governing PTC drainage, i.e., patients with completely blocked enterohepatic circulation. The blockage was observed to cause a delay in the excretion of CPZ due to hepatic dysfunction and the half-life of CPZ levels in serum was as long as 4.9 hours on the average. This is approximately the same as the half-life of 4.8 hours in hepatic dysfunction reported by Belaieff. Biliary concentration of CPZ reached their peak levels within the first 2 to 6 hours. The time to peak in cases with hepatic dysfunction was similar to that reported by observed in patients without hepatic dysfunction Yura et al. In our cases, however, peak biliary concentrations of CPZ were observed to be between 28 to 954 micrograms/ml with a mean of 320.5 micrograms/ml. These peak levels were lower than those reported by several investigators, but sufficiently effective concentrations seem to have been achieved in the bile even in jaundice because MIC80 values of CPZ are reported to be 6 to 10 micrograms/ml against E. coli, Klebsiella, and Enterobacter and 50 micrograms/ml against the most resistant Serratia. As mentioned above, the lowest peak biliary concentration was found to be 28 micrograms/ml and peak levels reached at least 50 micrograms/ml in 8 out of the 10 patients. Urinary concentrations of CPZ reached their peak levels within the first 30 minutes to 2 hours and CPZ urinary recovery ratio in 24 hours was 24.2 to 93.1% with a mean of 64.1%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Blood pressure response to conventional and low-dose enalapril in chronic renal failure

AIMS: In chronic renal failure, the clearance of most ACE inhibitors including enalapril is reduced. Hence, with conventional dosage, plasma enalaprilat may be markedly elevated. It is unclear whether this excess of drug exposure affords an improved control of blood pressure. The aim of the present study was to evaluate short-term blood pressure response to two different plasma levels of enalaprilat. METHODS: As part of an open, randomized, controlled trial of the effect of high and low dosage of enalapril on the progression of renal failure, short-term blood pressure response was evaluated. Data were analysed in all patients completing 3 months of follow-up. The patients were allocated to two trough plasma concentrations of enalaprilat, either above 50 ng ml(-1) (high) (n = 17) or below 10 ng ml(-1) (low) (n = 18), and the daily dose of enalapril titrated accordingly. RESULTS: Median (range) glomerular filtration rate (GFR) at baseline was 18 (7.9) in the high enalaprilat concentration group and 17 (7.3) ml min(-1) 1.73 m(2) in the low concentration group (NS). Nine patients in each group were on treatment with enalapril at baseline with a median daily dose of 5 mg in both the high (5-10) and low (2.5-20) concentration group. At 3 months' follow-up, the dose was 10 (2.5-30) and 1.9 (1.25-5) mg (P < 0.0001), respectively. After 3 months median trough concentrations of enalaprilat were 82.5 (22-244) ng ml(-1) and 9.1 (2.5-74.8) ng ml(-1) (P < 0.002). At baseline the median systolic blood pressures in the two groups were 140 (110-200) and 133 (110-165), in the high and low enalaprilat concentration groups, respectively, and after 3 months they were 135 (105-170) and 130 (105-170) mmHg (NS). Median diastolic blood pressure was 80 mmHg in each group both at baseline (65-100) and at follow-up (60-95) (NS). There was no difference between the groups in concomitant antihypertensive treatment (number of patients treated, mean daily dose) during the observation period. Proteinuria remained stable during the study period in both groups; patients in the high concentration group had higher plasma potassium concentrations at day 90 and patients in the low group experienced a slight increase in GFR. CONCLUSIONS: In moderate to severe chronic renal insufficiency the same degree of blood pressure control was achieved on low as well as moderate daily doses of enalapril. This was irrespective of concomitant antihypertensive treatment.