Preparation and evaluation of captopril loaded gastro-retentive zein based porous floating tablets.

In this study, gastro-retentive porous floating tablets of captopril based on zein are reported using l-menthol as a porogen. Tablets were prepared by the direct compression method. Removing of l-menthol through sublimation process generated pores in tablets, which decreased the density to promote floating over gastric fluid. Prepared tablets showed no floating lag time and prolong total floating time (>24 h). Drug release was found dependent upon porosity of tablets, an increase in porosity of tablets resulted in increased drug release, so it can be tuned by varying concentration of l-menthol. In addition to floating and sustained release properties, porous tablets showed robust mechanical behavior in wet conditions, which can enable them to withstand real gastric environment stress. In vivo studies using New Zealand rabbits also confirmed the prolonged gastric retention (24 h) and plasma drug concentration-time profile showed sustained release of captopril with higher Tmax and MRT as compared to marketed immediate-release tablets. Overall, it was concluded that effective gastric retention can be achieved using porous zein tablets using l-menthol as a porogen.

Facile Preparation of Boron and Nitrogen Codoped Green Emission Carbon Quantum Dots for Detection of Permanganate and Captopril.

A hydrothermal strategy for preparing boron and nitrogen codoped carbon quantum dots was studied using the precursors of p-amino salicylic acid, boric acid and ethylene glycol dimethacrylate. The boron and nitrogen codoped carbon quantum dots have high fluorescence intensity, good monodispersity, high stability, superior water solubility, and a fluorescence quantum yield of 19.6%. Their average size is 5 nm. Their maximum excitation and emission wavelengths are 380 and 520 nm, respectively. Permanganate (MnO4-) quenched boron and nitrogen codoped carbon quantum dots fluorescence through inner filter effect and static quenching effects. The linear relation between quenching efficiency and MnO4- concentration ranged from 0.05 to 60 µmol/L with a detection limit of 13 nmol/L. In the presence of captopril, MnO4- was reduced to Mn2+ and the fluorescence of boron and nitrogen codoped carbon quantum dots was recovered. The linear range between recovery and captopril concentration was from 0.1 to 60 µmol/L. The limit of detection was 0.03 µmol/L. The developed method can be employed as a sensitive fluorescence sensing platform for MnO4-. It has been successfully used for captopril detection in mouse plasma.

Simultaneous ultraperformance liquid chromatography/tandem mass spectrometry determination of four antihypertensive drugs in human plasma using hydrophilic-lipophilic balanced reversed-phase sorbents sample preparation protocol.

Therapeutic drug monitoring of angiotensin-converting enzyme inhibitors has a great impact on blood pressure control in patients with heart failure and hepatic and renal impairment. To provide an efficient tool for drug assessment in plasma, a UPLC-MS/MS method was developed for simultaneous determination of benazepril hydrochloride, fosinopril sodium, captopril and hydrochlorothiazide in human plasma samples. Solid phase extraction was applied for sample preparation using OASIS® hydrophilic-lipophilic balanced reversed-phase sorbents cartridges. Chromatographic separation was performed using an Agilent SB-C18 column and methanol-0.1% formic acid in water (95:5, v/v) as mobile phase, at flow rate 0.3 mL/min. Detection was accomplished using a tandem mass spectrometer. The method was validated according to US Food and Drug Administration guidelines. It showed good linearity over concentration ranges 5-400 ng/mL for benazepril hydrochloride, fosinopril sodium and hydrochlorothiazide and 100-3500 ng/mL for captopril. CV% values were <13.92% whereas the mean accuracy ranged from 94.50 to 113.82% for quality control samples and their extraction recoveries ranged from 90.60 to 99.38%. In conclusion, the present study revealed method selectivity and sensitivity; it can be applied for estimation of angiotensin converting enzyme inhibitors and hydrochlorothiazide in human plasma for dose adjustment and therapeutic drug monitoring.

Usability of Functional MRI in Clinical Studies for Fast and Reliable Assessment of Renal Perfusion and Quantification of Hemodynamic Effects on the Kidney.

The purpose of this study was to evaluate contrast-media-free arterial spin labeling, a technique of functional magnetic resonance imaging (MRI), for assessment of kidney perfusion in a clinical study. We examined renal perfusion by arterial spin labeling in 15 healthy adults using a clinical 1.5-T MRI system, twice under baseline conditions and 60 minutes after a single oral dose of 50 mg captopril. Data evaluation included assessment of interstudy and interrater reproducibility in addition to the pharmacological effect of captopril on kidney perfusion and a sample size calculation for potential application of the technique in pharmacological intervention studies. Interstudy reproducibility of cortical and medullary kidney perfusion was excellent (intraclass correlation coefficients 0.77 and 0.83, respectively). Interrater reproducibility was excellent in the cortex and good in the medulla (intraclass correlation coefficients 0.97 and 0.66, respectively). Ingestion of 50 mg captopril was associated with an 11% drop of systolic blood pressure and a rise in kidney perfusion by 22% in the cortex (369 ± 48 vs 452 ± 56 mL/[min·100 g], P < .001) and 26% in the medulla (157 ± 39 to 198 ± 45 ml/[min·100 g]; P < .01). Statistical power analysis revealed that a small sample size of only 6 participants is needed in a clinical trial to capture an equal change in kidney perfusion to the one induced by 50 mg captopril with a statistical power of 82% and an α error of 0.05. In conclusion, funtional MRI with arterial spin labeling is a reliable method for quantification of kidney perfusion and for fast assessment of pharmacologically induced renal perfusion changes, allowing low case numbers.

Simultaneous determination of ACE inhibitors and dexibuprofen in active pharmaceutical ingredient, formulations and human serum by RP-HPLC.

The contemporary work describes a rapid and cost effective reversed phase High Performance Liquid Chromatography (RP-HPLC) method for the quantification of Captopril, Lisinopril and Dexibuprofen (DXP) simultaneously in dosage formulations, active pharmaceutical ingredients and human serum. The chromatographic system included LC-20A pump, Sil-20A auto sampler and SPD-20A UV/visible detector. The estimation was carried out by using a C18 (5µm, 250 ×4.6 mm) column with mobile phase methanol: water (80:20 v/v, pH 3.0) at 230 nm with a flow rate of 1.0 ml•min-1. The retention time of Dexibuprofen was 5.4 min while that of Captopril and Lisinopril were found to be 3.2 and 1.8 minutes respectively. There was no considerable variation exists in between the tested drug spiked in serum and the extent recovered, without interference of serum in concurrent approximation. The method developed was found to be precise, selective and validated for precision, linearity, specificity, accuracy, limit of detection and limit of quantitation. There is no such method reported earlier for the determination of ACE Inhibitors and DXP simultaneously. The present study helps in assessing the co-administration of both drugs in treatment and can be employed for quality control analysis and drug-drug interaction studies.

Laser induced thermal lens microscopy for highly sensitive determination of captopril.

In this work, a combined flow injection-photo thermal lens microscopy (FI-PTLM) system was used for highly sensitive determination of captopril as an angiotensin-converting enzyme inhibitor. Captopril has no absorption in the visible range, but due to its thiol group could interact with gold nanoparticles (GNPs). GNPs, because of their surface plasmon resonance (SPR), have absorption in the visible range, but their interaction with a low concentration of captopril shows no effective change in UV-Vis spectrophotometry because their aggregation is slight. On the contrary, at the same condition, the PTLM with a visible light source enables sensitive measurement of this compound. The thiol group of captopril binds to the surface of GNPs and decreases the SPR. At the optimum condition in the focal volume of 2.68 fL (f=10-15), the obtained range of linearity was 50-800 nM. The developed method was successfully applied for the determination of captopril in human serum and pharmaceutical samples.

Pharmacodynamics of alacepril in healthy cats.

Objectives The aims of this study were to investigate the pharmacodynamics of alacepril and to determine the appropriate dose for clinical usage in cats. Methods Six experimental cats were used. Each cat received alacepril orally at a single dose of 1 mg/kg, 2 mg/kg and 3 mg/kg. Blood samples were collected before administration and at 2, 4, 6, 8, 12, 24, 36, 48 and 72 h after administration to measure serum angiotensin converting enzyme (ACE) activity. Systolic blood pressure was also measured at the same time point. Results Dose-dependent inhibition of ACE activity was observed. Doses of 2 mg/kg and 3 mg/kg alacepril were considered to effectively inhibit ACE activity. There were no significant differences in systolic blood pressue among groups at any time point. Conclusions and relevance Alacepril 2-3 mg/kg q24h may be an appropriate dosage for clinical use in cats.

Electrochemically reduced graphene and iridium oxide nanoparticles for inhibition-based angiotensin-converting enzyme inhibitor detection.

In this work, a novel biosensor based on electrochemically reduced graphene oxide and iridium oxide nanoparticles for the detection of angiotensin-converting enzyme inhibitor drug, captopril, is presented. For the preparation of the biosensor, tyrosinase is immobilized onto screen printed electrode by using 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide and N-Hydroxysuccinimide coupling reagents, in electrochemically reduced graphene oxide and iridium oxide nanoparticles matrix. Biosensor response is characterized towards catechol, in terms of graphene oxide concentration, number of cycles to reduce graphene oxide, volume of iridium oxide nanoparticles and tyrosinase solution. The designed biosensor is used to inhibit tyrosinase activity by Captopril, which is generally used to treat congestive heart failure. It is an angiotensin-converting enzyme inhibitor that operates via chelating copper at the active site of tyrosinase and thioquinone formation. The captopril detections using both inhibition ways are very sensitive with low limits of detection: 0.019µM and 0.008µM for chelating copper at the active site of tyrosinase and thioquinone formation, respectively. The proposed methods have been successfully applied in captopril determination in spiked human serum and pharmaceutical dosage forms with acceptable recovery values.

Effects of curcumin and captopril on the functions of kidney and nerve in streptozotocin-induced diabetic rats: role of angiotensin converting enzyme 1.

Oxidative stress and inflammation are involved in the development and progression of diabetes and its complications. The renin-angiotensin system also plays an important role in the pathogenesis of diabetes and its complications. We hypothesized that curcumin and captopril would restore the kidney and nerve functions of diabetic rats through their angiotensin converting enzyme 1 (ACE1) inhibiting activity as well as their antioxidant and anti-inflammatory effects. Diabetes was induced by a single intraperitoneal injection of streptozotocin (100 mg·kg(-1) body weight). One week after induction of diabetes, rats were treated with 100 mg·kg(-1)·day(-1) curcumin or 50 mg·kg(-1)·day(-1) captopril orally for 6 weeks. Compared with diabetic control rats, curcumin- or captopril-treated diabetic rats had significantly improved blood glucose, lipid profile, kidney/body weight ratio, serum creatinine, blood urea nitrogen (BUN), and pain thresholds assessed by Von Frey filaments, hot plate test, and tail-flick test. Diabetic control rats showed increased levels of total peroxide, renal and neural tumor necrosis factor-α and interleukin-10, and renal ACE1 compared with nondiabetic rats. Although treatment with either curcumin or captopril restored the altered variables, captopril was more effective in reducing these variables. ACE1 was positively correlated with BUN and creatinine and negatively correlated with paw withdrawal threshold, hot plate reaction time, and tail-flick latency, suggesting a possible causal relationship. We conclude that curcumin and captopril protect against diabetic nephropathy and neuropathy by inhibiting ACE1 as well as oxidation and inflammation. These findings suggest that curcumin and captopril may have a role in the treatment of diabetic nephropathy and neuropathy.

Determination of zofenopril and its active metabolite in human plasma using high-performance liquid chromatography combined with a triple-quadruple tandem mass spectrometer.

A simple, selective and sensitive LC-MS-MS method has been developed and validated to simultaneously quantify zofenopril and its active metabolite zofenoprilat in human plasma, using diazepam as internal standard. 1,4-Dithiothreitol was used as a reducer to release and stabilize the thiol group of zofenoprilat from dimer and mixed forms with endogenous thiols in the treatment of plasma samples. After a liquid-liquid extraction with methyl tert-butyl ether under acidic conditions, the post-treatment samples were analyzed on an Agilent ZORBAX Eclipse XDB-C8 column interfaced with a triple-quadruple tandem mass spectrometer using positive electrospray ionization. A solution of methanol and 0.1% formic acid solution (85 : 15, v/v) was used as the isocratic mobile phase with a flow rate of 0.2 mL/min. The method was validated to demonstrate the specificity, lower limit of quantitation, accuracy and precision of measurements. The validated LC-MS-MS method has been successfully applied to study the pharmacokinetics of zofenopril calcium in healthy Chinese volunteers.

Electropolymerization of taurine on gold surface and its sensory application for determination of captopril in undiluted human serum.

Polytaurine film was electrodeposited on gold (Au) electrode through cyclic voltammetry from taurine and phosphate buffer solution. The electrocatalytic effect of polytaurine modified Au (PT/Au) electrode was investigated for electro-oxidation of captopril (CAP). Electrocatalytical activity of PT/Au electrode was studied using cyclic voltammetry (CV), chronoamperometry and differential pulse voltammetry (DPV). DPV was used to evaluate the analytical performance of CAP in the presence of phosphate buffer solution and good limit of detection was obtained by this sensor. The experimental conditions influencing the determination of CAP were optimized and under optimal conditions, the oxidation peak current was proportional to CAP concentration in the range of 0.06-0.2 µM, while the detection limit was 0.03 µM (S/N=3). The results revealed that PT promotes the rate of oxidation by increasing the peak current. Finally, the applicability of the method to direct assay of human serum is described. The proposed sensor was successfully applied to determine cadaverine in fish samples, yielding satisfactory results. The spiked recoveries were in the range of 96.0-105.0%.

Permanganate-bromide-silver nanoparticles as a new chemiluminescence system and its application to captopril determination.

A novel chemiluminescence (CL) system based on the oxidation of bromide by permanganate in sulfuric acid medium is introduced. The enhancing effect of silver nanoparticles (NPs), synthesized by chemical reduction method, on this reaction was studied. It was demonstrated that spherical silver nanoparticles with average size of 18 nm had a most remarkable catalytic effect on this reaction. CL emission wavelengths and UV-vis spectra were used to characterize the system and propose a possible mechanism. Furthermore, it was found that captopril inhibits the action of NPs and decreases the intensity of CL. Based on this phenomenon, a new CL method was developed for the determination of captopril in the 3.0 × 10(-10) to 1.0 × 10(-7) mol L(-1) concentration range with a detection limit (3s) of 0.12 nmol L(-1). The method was successfully applied to the determination of captopril in pharmaceutical formulations, human urine and serum samples.

Development and validation of a simple and sensitive HPLC-UV method for the determination of captopril in human plasma using a new derivatizing reagent 2-naphthyl propiolate.

In this study, a simple, sensitive and reliable HPLC-UV method applying rapid sample preparation technique for the determination of captopril in human plasma was developed and validated. The method is based on pre-column derivatization of captopril and 2-propene-1-thiol (internal standard) with a new reagent 2-naphthyl propiolate. Sample clean-up, derivatization and extraction were carried out in two steps, totally less than 30min. The extracts were chromatographed on a C18 column (5µm, 150mm×4.6mmi.d.). The mobile phase consisted of methanol (75%, v/v) and phosphate buffer (25%, pH=8, 0.01M). UV detection was performed at 290nm. To obtain the best reaction yield, the factors that could influence the derivatization process, including the concentration of derivatization reagent, pH of sample solution and temperature were investigated in detail and optimized using Box-Behnken response surface methodology. Under optimized conditions the average extraction recovery of captopril and internal standard were >86%. The achieved lower limit of quantification (LLOQ) was 3ng/mL; the assay exhibited a linear dynamic range of 3-2000ng/mL with correlation coefficient (r(2)) of ≥0.99. The precision was satisfactory in the whole calibration range with RSD of 5.9-12.4% (accuracy: from 97.5% to 93.6%) and of 6.4-12.8% (accuracy: from 97.3% to 95.2%) for intra- and inter-assay, respectively. The method stability was confirmed in a series of experiments including: freeze-thaw, short- and long-term stability testing. Lastly, the developed method was successfully applied to the bioequivalence study of captopril administrated as a single oral dose (50mg) to 12 healthy male volunteers.

Determination of captopril by high-performance liquid chromatography with direct electrogenerated chemiluminescence.

Captopril exhibit electrogenerated chemiluminescence (ECL) in NaNO(3) solution when constant current is exerted. Based on this observation, a direct ECL method coupled with high-performance liquid chromatography (HPLC) separation is developed for determination of captopril in human serum. Factors affected the ECL emission are investigated. Under the optimal conditions, the ECL intensity has a linear relationship with the concentration of captopril in the range of 4.0×10(-6)-2.0×10(-3) g mL(-1) and the detection limit is 2×10(-6) g mL(-1) (S/N=3). Compared with the common electrogenerated chemiluminescence experiments, the developed method need no any other fluorescence additives.

Development and validation of a liquid chromatography-tandem mass spectrometry method for the determination of zofenopril and its active metabolite zofenoprilat in human plasma.

A novel, sensitive and rapid liquid chromatographic-electrospray ionization mass spectrometric method was developed and validated for the determination of zofenopril and its active metabolite zofenoprilat in human plasma. The method was based on a single extraction step using methyl tert-butyl ether and did not require chemical derivatization. The chromatographic conditions were optimized; separation was performed on a phenyl-hexyl column (5µm, 250mm×4.6mm i.d.) with a mobile phase consisting of a solution of methanol and water (95:5, v/v) that also contained 0.1% of formic acid. A flow rate of 1.0mL/min was used. Zofenopril, zofenoprilat and the internal standard (IS) fosinopril sodium were measured using an electrospray ion source in a positive reaction monitoring mode. Linear calibration curves were generated for zofenopril concentrations between 0.1052 and 1052ng/mL and for zofenoprilat concentrations between 0.2508 and 2508ng/mL. In both cases, the coefficients of determination were greater than 0.995. The extraction recovery for zofenopril was 93.5% on average. It was 92.5% for zofenoprilat. The inter- and intra-batch precision and accuracy for both zofenopril and zofenoprilat were higher than 14%. The method was applied to measure the concentrations of zofenopril and zofenoprilat in plasma samples.

Assessment of liquid captopril formulations used in children.

OBJECTIVE: Unlicensed liquid captopril formulations are commonly used to treat children with heart disease. This study assessed the bioequivalence of two liquid preparations against a licensed tablet form. DESIGN: An open label, single dose, three-treatment, three-period, crossover trial. SETTING: Outpatient. PATIENTS: Healthy adult volunteers (n=18). INTERVENTIONS: Each subject was randomly assigned to one of six dosing sequences, and dosed with 25 mg captopril on each of three dosing visits separated by a washout of at least 14 days. Blood samples for pharmacokinetic analysis were taken at regular intervals (0 min to 10 h) post-dose. MAIN OUTCOME MEASURES: Bioequivalence of the formulations would be concluded if the 90% CI for the estimated ratio of the means of C(max) (maximum plasma concentrations) and area under curve(AUC) (extent of absorption) lay entirely within the range 0.8 to 1.25 RESULTS: Both liquid formulations failed the bioequivalence assessment with respect to C(max) and AUC. The 90% CI of the mean ratios of liquid/licensed tablet for both C(max) and AUC, fell outside the 0.8 to 1.25 limits. There was also considerable within-subject variability in C(max) (97.5%) and AUC (78.5%). CONCLUSIONS: Unlicensed captopril formulations are not bioequivalent to the licensed tablet form, or to each other, and so cannot be assumed to behave similarly in therapeutic use. Thus formulation substitution must be done with care and may require a period of increased monitoring of the patient. There is also significant within-subject variability in performance which has clinical implications with respect to titrating to an optimum therapeutic dose.

Determination of free captopril in human plasma by liquid chromatography with mass spectrometry detection.

A new simple, sensitive and selective liquid chromatography coupled with mass spectrometry (LC/MS) method for quantification of captopril after precolumn derivatization with p-bromo-phenacyl-bromide in human plasma was validated. Plasma samples were analysed on a monolithic column (Cromolith Performance-RP 18e, 100 mm x 4.6 mm I.D., 3 microm) under isocratic conditions using a mobile phase of a 40:60 (v/v) mixture of acetonitrile and 0.1% (v/v) formic acid in water. The flow rate was 1 mL/min at the column temperature of 30 degrees C. In these chromatographic conditions, the retention time was 4.4 min for captopril derivative. The detection of the analyte was in MRM mode using an ion trap mass spectrometer with electrospray positive ionisation. The monitored ions were 216, 253, 255, 268, 270 m/z derived from 415 m/z for derivatized captopril. The sample preparation was very simple and consisted in plasma protein precipitation from 0.2 mL plasma using 0.3 mL methanol after the derivatization reaction was completed. Calibration curves were generated over the range of 10-3000 ng/mL with values for coefficient of correlation greater than 0.993 and by using a weighted (1/y(2)) quadratic regression. The values for precision (CV %) and accuracy (relative error %) at quantification limit were less than 9.9% and 3.9%, for within- and between-run, respectively. The mean recovery of the analyte was 99%. Derivatized samples demonstrated good short-term, long-term, post-preparative and freeze-thaw stability. This is the first reported LC-MS/MS method for analysis of captopril in human plasma that uses protein precipitation as sample processing procedure. The method is very simple and allows obtaining a very good recovery of the analyte. The validated LC-MS/MS method has been applied to a pharmacokinetic study of 50mg captopril tablets on healthy volunteers.

Rapid analysis of captopril in human plasma and pharmaceutical preparations by headspace solid phase microextraction based on polypyrrole film coupled to ion mobility spectrometry.

A rapid, simple, and sensitive headspace solid phase microextraction coupled to ion mobility spectrometry (HS-SPME-IMS) method is presented for analysis of the highly specific angiotensin-converting enzyme (ACE) inhibitor, captopril (CAP). Positive ion mobility spectra of CAP were acquired with an ion mobility spectrometer equipped with a corona discharge ionization source. Mass-to-mobility correlation equation was used to identify product ions. A dodecylsulfate-doped polypyrrole (PPy-DS) coating was used as a fiber for SPME. The results showed that PPy-DS based SPME fiber was suitable for successfully extracting CAP from human blood plasma and pharmaceutical samples. The HS-SPME-IMS method provided good repeatability (R.S.D.s<4%) for aqueous and spiked plasma samples. The calibration graphs were linear in the range of 10-300 ng mL(-1) (R(2)>0.99) and detection limits were 7.5 ng mL(-1) for aqueous and 6.3 ng mL(-1) for plasma blank samples. Finally, a standard addition calibration method was applied to HS-SPME-IMS technique for the analysis of blood plasma samples and tablets. Purpose method seemed to be suitable for the analysis of CAP in plasma samples as it is not time consuming (state total time from sample preparation to analysis), it required only small quantities of the sample, and no derivatization was required.

Assay of free captopril in human plasma as monobromobimane derivative, using RPLC/(+)ESI/MS/MS: validation aspects and bioequivalence evaluation.

A sensitive method for determination of free captopril as monobromobimane derivative in plasma samples is discussed. The internal standard (IS) was 5-methoxy-1H-benzimidazole-2-thiol. Derivatization with monobromobimane immediately after blood collection and plasma preparation prevents oxidation of captopril to the corresponding disulfide compound and enhances the ionization yield. Consequently, derivatization enhances sample stability and detection sensitivity. Addition of the internal standard was made immediately after plasma preparation. The internal standard was also derivatized by monobromobimane, as it contains a thiol functional group. Preparation of plasma samples containing captopril and IS derivatives was based upon protein precipitation through addition of acetonitrile, in a volumetric ratio 1:2. The reversed-phase liquid chromatographic separation was achieved on a rapid resolution cartridge Zorbax SB-C(18), monitored through positive electrospray ionization and tandem MS detection using the multiple-reaction monitoring mode. Transitions were 408-362 amu for the captopril derivative and 371-260 amu for the internal standard derivative. The kinetics of captopril oxidation to the corresponding disulfide compound in plasma matrix was also studied using the proposed method. A linear log-log calibration was obtained over the concentration interval 2.5-750 ng/mL. A low limit of quantitation in the 2.5 ng/mL range was obtained. The analytical method was fully validated and successfully applied in a three-way, three-period, single-dose (50 mg), block-randomized bioequivalence study for two pharmaceutical formulations (captopril LPH 25 and 50 mg) against the comparator Capoten 50 mg.

Long-term plasma levels and dose modulation of alacepril in patients with chronic renal failure.

Because most angiotensin-converting enzyme inhibitors are excreted into urine, any decrease in renal function increases the plasma levels of these drugs. This study was designed to investigate the appropriate doses of alacepril in patients with chronic renal failure. The total plasma concentration of captopril, an active metabolite of alacepril, was measured in 47 patients with chronic renal failure or normal renal function. Fifteen patients on chronic hemodialysis were also enrolled in this study. In patients treated with 12.5, 25 and 50 mg alacepril, the plasma concentration of captopril was linearly correlated with serum creatinine and creatinine clearance (Ccr). There was an approximately 40% decrease of the plasma captopril concentration after 4 h of hemodialysis. Among patients treated with 25 or 50 mg alacepril for 4.5 years, the plasma concentration of captopril gradually increased along with an increase in serum creatinine (from 2.0 to 5.8, and from 1.9 to 7.1 mg/dL, respectively). Although the plasma concentration of captopril was higher in the 50 mg group, the increase in serum creatinine during this period was not different between the two groups. The plasma aldosterone concentration did not increase during this period. These data suggest that alacepril should be reduced from 50 to 25 and 12.5 mg/day in patients with a serum creatinine level of greater than 2-3 and 4-6 mg/dL, respectively, in order to maintain a plasma level equivalent to that in subjects with normal renal function receiving 50 mg/day alacepril. For patients on chronic hemodialysis, 12.5 mg alacepril is the appropriate dose.