benazepril and benazeprilat

Benazepril is a nonsulfhydryl ACE inhibitor with favorable pharmacodynamic and pharmacokinetic properties, well-established antihypertensive effects and a good tolerability profile. Recent clinical studies have demonstrated that patients treated with benazepril alone or in combination with hydrochlorothiazide or amlodipine may achieve beneficial renal outcomes that extend beyond blood pressure control. Furthermore, the recent Avoiding Cardiovascular Events Through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial showed decreased cardiovascular morbidity and mortality with benazepril when administered as a cotreatment. An additional novel therapeutic area for benazepril is atrial fibrillation. Differences between combination therapies have implications for which patients may be best suited to particular interventions, and further studies are required to fully ascertain this potential.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Atrial Fibrillation; Benzazepines; Calcium Channel Blockers; Diuretics; Drug Therapy, Combination; Humans; Hypertension; Kidney; Practice Guidelines as Topic; Prodrugs; Societies, Medical

Pharmacokinetic and pharmacodynamic (PK/PD) properties of the angiotensin-converting enzyme inhibitor (ACEI) benazeprilat have not been evaluated in horses. This study was designed to establish PK profiles for benazepril and benazeprilat after intravenous (IV) and oral (PO) administration of benazepril using a PK/PD model. This study also aims to determine the effects of benazeprilat on serum angiotensin converting enzyme (ACE), selecting the most appropriate dose that suppresses ACE activity. Six healthy horses in a crossover design received IV benazepril at 0.50mg/kg and PO at doses 0 (placebo), 0.25, 0.50 and 1.00mg/kg. Blood pressures (BP) were measured and blood samples were obtained at different times in order to measure serum drug concentrations and serum ACE activity, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and spectrophotometry, respectively. Systemic bioavailability of benazeprilat after PO benazepril was 3-4%. Maximum ACE inhibitions from baseline were 99.63% (IV benazepril), 6.77% (placebo) and 78.91%, 85.74% and 89.51% (for the three PO benazepril doses). Significant differences in BP were not found. Although oral availability was low, benazeprilat 1.00mg/kg, reached sufficient serum concentrations to induce long lasting serum ACE inhibitions (between 88 and 50%) for the first 48h. Additional research on benazepril administration in equine patients is indicated.

Topics: Administration, Intravenous; Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Biological Availability; Cross-Over Studies; Horses; Male

To compare the bioequivalence and 'switchability' of two formulations of benazepril (tablet and liquid) after oral administration.. Randomised cross-over design, followed by parallel comparison.. Twelve mixed-breed dogs were administered either a tablet (Group A) or liquid formulation (Group B) of benazepril orally at 0.45 mg/kg daily for 4 days. With no washout period, the dogs then received the alternative treatment at the same dose for a further 4 days. Blood samples taken prior to treatment and serially after treatment were analysed for plasma concentrations of benazepril and benazeprilat and the activity and concentration of angiotensin-converting enzyme (ACE). The calculated percentage inhibition of ACE was defined as the primary outcome variable.. No statistically significant differences were found between groups A and B for any variable evaluated. The mean (± SD) percentage of ACE inhibition was 85.5 ± 7.04% for the liquid formulation and 85.9 ± 6.66% for the tablet formulation. The mean of the ratios was 1.00 (80% confidence interval 0.96-1.04). No evaluated effect term (sequence, formulation or period) had any statistical effect on any outcome variable.. This study supports a conclusion that, based on pharmacodynamic response, the liquid formulation of benazepril is bioequivalent to the reference tablet formulation. Further, the lack of a sequence effect supports the switchability of these two formulations.

Topics: Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Animals; Area Under Curve; Benzazepines; Cross-Over Studies; Dogs; Female; Male; Peptidyl-Dipeptidase A; Therapeutic Equivalency

To examine whether an angiotensin converting enzyme (ACE) inhibitor, benazepril, can be transformed to the active metabolite, benazeprilat, by severely injured liver of dogs with ascitic heartworm disease, benazepril hydrochloride was administered orally to dogs once daily for 7 consecutive days at a dose rate of 0.29 mg/kg to 0.63 mg/kg of body weight, and plasma benazepril and benazeprilat concentrations were determined on the 1st and 7th administration days. In 7 dogs with ascitic pulmonary heartworm disease, plasma benazeprilat concentrations tended to be higher than in 7 control dogs both on the 1st and 7th administration days. The peak concentration and area under the concentration-time curve tended to be greater in dogs of the ascites group than in control dogs, but the statistics could not detect significant differences in the time to peak concentration and t(1/2) between the control and ascites groups. Plasma ACE activities decreased after administration of benazepril. In dogs with ascitic heartworm disease, benazepril was readily transformed to benazeprilat by the liver, and was effective for suppression of plasma ACE activity.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Ascites; Benzazepines; Biotransformation; Dirofilariasis; Dog Diseases; Dogs; Female; Liver; Liver Diseases, Parasitic; Male

The effect of renal insufficiency was studied on the pharmacokinetics (PK) and pharmacodynamics (PD) of the angiotensin-converting enzyme (ACE) inhibitor benazepril in cats. The active metabolite of benazepril, benazeprilat, is eliminated principally ( approximately 85%) via biliary excretion in cats. A total of 20 control animals and 32 cats with moderate renal insufficiency induced by partial nephrectomy were used. Assessments were made at steady state after treatment with placebo or benazepril (0.25-2 mg/kg) once daily for a minimum of 10 days. The PK endpoint was the AUC (0-->24 h) of total plasma benazeprilat. The PD endpoints were systolic, diastolic and mean blood pressures (respectively SBP, DBP and MBP) measured by telemetry, and plasma ACE activity, assessed by an ex vivo assay. Renal function was assessed by glomerular filtration rate (GFR), measured by inulin clearance, and plasma creatinine concentrations (1/PCr). As compared with control animals, the renal insufficient cats had a 78% reduction in GFR (0.57 +/- 0.41 mL/min kg), increased plasma creatinine (2.7 +/- 1.0 mg/dL), urea (44.0 +/- 11.9 mg/dL) and ACE activity, and moderately increased blood pressure (SBP 171.8 +/- 5.1 mmHg) (all parameters P < 0.05). Renal insufficient cats receiving benazepril had significantly (P < 0.05) lower SBP, DBP, MBP and ACE, and higher GFR values as compared with placebo-treated animals. There were no significant differences in SBP, DBP, MBP, benazeprilat or ACE values according to the degree of renal insufficiency in cats receiving benazepril. It is concluded that no dose adjustment of benazepril is necessary in cats with moderate renal insufficiency.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Area Under Curve; Benzazepines; Blood Pressure; Cat Diseases; Cats; Creatinine; Female; Kidney; Kidney Function Tests; Male; Renal Insufficiency

Potential effects of the coadministration of single doses of aspirin (325 mg) and of benazepril hydrochloride (20 mg) on the pharmacokinetics and the metabolism of these two drugs were evaluated in 12 healthy subjects. Plasma concentration profiles of benazepril, its active metabolite benazeprilat, and total salicylic acid were determined together with urinary excretion of benazeprilat, salicylic acid, salicyluric acid, and salicylate glucuronides. Almost superimposable plasma profiles of benazepril, benazeprilat, and total salicylic acid were achieved with the drugs given alone and concomitantly. The coadministration of benazepril hydrochloride and aspirin did not modify the pharmacokinetics or the metabolism of the two drugs.

Topics: Adult; Analysis of Variance; Angiotensin-Converting Enzyme Inhibitors; Aspirin; Benzazepines; Chromatography, Gas; Drug Interactions; Hippurates; Humans; Hydrolysis; Male; Quality Control; Reproducibility of Results; Tablets

A simple, specific, and rapid kinetic study of benazepril (BNZ) hydrolysis was developed and validated using HPLC. BNZ was degraded using 0.1 N sodium hydroxide at room temperature to produce benazeprilat, which is an active metabolite of BNZ and acts as an angiotensin-converting enzyme inhibitor. Analysis was carried out using an Athena C18 column (4.6 × 250 mm, 5 µm particle size). The mobile phase consists of a mixture of phosphate buffer (pH 4.5) and acetonitrile (53 + 47, v/v) at a flow rate of 1 mL/min. UV detection was accomplished at 242 nm using moexipril as the internal standard. The method was validated according to International Conference on Harmonization guidelines, and the calibration curve was linear over the range 10-100 µg/mL, with acceptable accuracy and precision. Kinetic profiling of the hydrolysis was shown to follow pseudo-first-order kinetics. The method was applied to the assay of BNZ in combined dosage form with no interference from other ingredients. The obtained results were statistically compared with those of the official method, showing no significant difference.

Topics: Acetonitriles; Angiotensin-Converting Enzyme Inhibitors; Benzazepines; Buffers; Calibration; Capsules; Chromatography, High Pressure Liquid; Hydrogen-Ion Concentration; Hydrolysis; Inactivation, Metabolic; Kinetics; Reproducibility of Results; Sodium Hydroxide; Tetrahydroisoquinolines

The study aims to develop a rapid, sensitive and specified method of liquid chromatography with heated electrospray ionization tandem mass spectrometry (LC-HESI/MS/MS) for simultaneous determination of amlodipine, benazepril and benazeprilat in human plasma using amlodipine-d4 and ubenimex as internal standards (ISs). Selected reaction monitoring (SRM) with heated electrospray ionization (HESI) was used in the positive mode for mass spectrometric detection. Analytes and ISs were extracted from plasma by simple protein precipitation. The reconstituted samples were chromatographed on a C18 (100 mm x 4.6 mm, 5 microm) column with mixture of methanol-acetonitrile-5 mmol.L- ammonium acetate-formic acid (30 : 30 : 40 : 0.1) as mobile phase at a flow rate of 0.6 mL.min-1. The standard curves were demonstrated to be linear in the range of 0.02 to 6.00 ng.mL-1 for amlodipine, 0.2 to 1,500 ng.mL-1 for benazepril and benazeprilat with r2>0.99 for each analyte. The lower limit of quantitation was identifiable and reproducible at 0.02, 0.2 and 0.2 ng mL-1 for amlodipine, benazepril and benazeprilat, respectively. The intra-day and inter-day precision and accuracy results were within the acceptable limit across all concentrations. The plasma samples were stable after four freeze-thaw cycles and being stored for 93 days at -20 degrees C. The method was applied to a pharmacokinetic study of a fixed-dose combination of amlodipine and benazepril on Chinese healthy volunteers.

Topics: Administration, Oral; Amlodipine; Benzazepines; Chromatography, Liquid; Humans; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry

A rapid, simple, sensitive and specific LC-MS/MS method has been developed and validated for the simultaneous estimation of amlodipine (AML), benazepril (BEN) and benazeprilat (BNT) using eplerenone and torsemide as internal standards (IS). The Xevo TQD LC-MS/MS was operated under the multiple-reaction monitoring mode using electrospray ionization. Sample preparation involves both extraction and precipitation techniques. The reconstituted samples were chromatographed on Acquity UPLC BEH C18 (50mm×2.1mm, 1.7μm) column by pumping 0.1% formic acid and acetonitrile in a gradient mode at a flow rate of 0.45ml/min. A detailed validation of the method was performed as per the FDA guidelines and the standard curves were found to be linear in the range of 0.1-5ng/ml for AML; 5-1200ng/ml for both BEN and BNT. The intra-day and inter-day precision and accuracy results were within the acceptable limits. A run time of 2.5min for each sample made it possible to analyze more than 300 human plasma samples per day. The developed assay method was successfully applied to a bioequivalence study in human volunteers.

Topics: Amlodipine; Benzazepines; Chromatography, High Pressure Liquid; Humans; Plasma; Reproducibility of Results; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry; Therapeutic Equivalency

We aim to develop a rapid, simple, sensitive and specific LC-MS/MS method for the simultaneous quantification of lercanidipine, benazepril and benazeprilat in plasma. It is performed on the Agilent 6410 LC-MS/MS under the multiple-reaction monitoring (MRM) mode with electrospray ionization. Gliclazide was used as the internal standard (IS). Analytes and IS were extracted from plasma by solid-phase extraction. The reconstituted samples were chromatographed on a Diamond C₁₈(150 mm × 4.6 mm, 5 μm) column. The mobile phase was composed of 0.1% acetic acid-acetonitrile (50:50, v/v), with gradient flow rates: 0.6 mL/min (0-4.55 min); 4.55-4.65 min, 1 mL/min; 1 mL/min (4.65-9.5 min); 9.5-9.6 min, 0.6 mL/min; 0.6 mL/min (9.6-10 min). Method validation demonstrated that the method was of satisfactory specificity, sensitivity, precision and accuracy in linear ranges of 1-2000 ng/mL for lercanidipine, 1-2000 ng/mL for benazepril and 1-1600 ng/mL for benazeprilat, respectively. The precision (RSD%) was better than 15, and the lower limit of quantitation was identifiable and reproducible at 1 ng/mL for the three analytes. The plasma samples were stable after being stored for more than 60 days and after two freeze-thaw cycles (-20 to -25 °C). It is demonstrated that this method was successfully applied to samples from a toxicokinetics study of a compound of lercanidipine and benazepril in beagle dogs.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Chromatography, High Pressure Liquid; Dihydropyridines; Dogs; Sensitivity and Specificity; Tandem Mass Spectrometry

A sensitive and accurate high-performance liquid chromatography (HPLC) method with ultraviolet (UV) detector was developed and validated for simultaneous determination of benazepril (BZL) and its active metabolite, benazeprilat (BZT), in human plasma. The plasma sample, after spiked with riluzole as an internal standard (IS), was subjected to a solid-phase extraction (SPE) prior to a HPLC analysis. Chromatographic separations were achieved on a Hypersil BDS C(18) (300 mm x 4.6mm, 5 microm). The mobile phase consisted of phosphate buffer (pH 2.6; 10mM) and acetonitrile mixture in a gradient mode. Detection was carried out at a wavelength of 237 nm. The retention times of BZL, BZT and IS were at about 6.2, 15.4 and 16.2 min, respectively. The calibration curve was linear in the range of 20-2000 ng/mL for both BZL and BZT (r(2)>0.997). At three quality control concentrations of 100, 500, and 1500 ng/mL, the intra-day and inter-day relative standard deviation ranged from 2.8 to 8.6% for BZL and from 2.2 to 8.5% for BZT, while the mean absolute percentage error ranged from -7.5 to 6.7% for BZL and from -6.0 to 3.2% for BZT. The limit of detection (LOD) was 10 ng/mL and the limit of quantification (LOQ) was 20 ng/mL for both BZL and BZT in human plasma. The method was successfully applied to bioequivalence evaluation of benazepril hydrochloride formulations in healthy Chinese.

Topics: Acetonitriles; Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Area Under Curve; Asian People; Benzazepines; Buffers; Calibration; Chemistry, Pharmaceutical; Chromatography, High Pressure Liquid; Drug Stability; Freezing; Humans; Hydrogen-Ion Concentration; Male; Molecular Structure; Phosphates; Reference Standards; Reproducibility of Results; Riluzole; Sensitivity and Specificity; Solid Phase Extraction; Spectrophotometry, Ultraviolet; Tablets; Temperature; Therapeutic Equivalency; Time Factors

A new method was developed and fully validated for the quantitation of benazepril, benazeprilat and hydrochlorothiazide in human plasma. Sample pretreatment was achieved by solid-phase extraction (SPE) using Oasis HLB cartridges. The extracts were analysed by high-performance liquid chromatography (HPLC) coupled to a single-quadrupole mass spectrometer (MS) with an electrospray ionization interface. The MS system was operated in selected ion monitoring (SIM) modes. HPLC was performed isocratically on a reversed-phase porous graphitized carbon (PGC) analytical column (2.1 x 125.0 mm i.d., particle size 5 microm). The mobile phase consisted of 55% acetonitrile in water containing 0.3% v/v formic acid and pumped at a flow rate of 0.15 ml min(-1). Chlorthalidone was used as the internal standard (IS) for quantitation. The assay was linear over a concentration range of 5.0-500 ng ml(-1) for all the compounds analysed, with a limit of quantitation of 5 ng ml(-1) for all the compounds. Quality control (QC) samples (5, 10, 100 and 500 ng ml(-1)) in five replicates from three different runs of analyses demonstrated intra-assay precision (coefficient of variation (CV) < or =14.6%), inter-assay precision (CV < or = 5.6%) and overall accuracy (relative error less than -8.0%). The method can be used to quantify benazepril, benazeprilat and hydrochlorothiazide in human plasma, covering a variety of pharmacokinetic or bioequivalence studies.

Topics: Antihypertensive Agents; Benzazepines; Calibration; Chromatography, High Pressure Liquid; Humans; Hydrochlorothiazide; Reproducibility of Results; Spectrometry, Mass, Electrospray Ionization

An analytical method for simultaneous determination of benazepril and its active metabolite, benazeprilat, in human plasma by high-performance liquid chromatography/electrospray-mass spectrometry was developed and validated. Rutaecarpine was selected as the internal standard. The separation was achieved on a C(18) column with acetonitrile and aqueous solution (0.1% formic acid) as mobile phase with a gradient mode. The quantification of target compounds was using a selective ionization recording at m/z 425.5 for benazepril, m/z 397.5 for benzeprilat and m/z 288.3 for rutaecarpine. The correlation coefficients of the calibration curves were better than 0.992 (n = 6), in the range of 6.67-666.67 ng/ml for benazepril and benazeprilat. The inter- and intra-day accuracy, precision, linear range had been investigated in detail. The method can be used to assess the bioavailability and pharmacokinetics of the drug.

Topics: Angiotensin-Converting Enzyme Inhibitors; Benzazepines; Biological Availability; Calibration; Chromatography, High Pressure Liquid; Humans; Reproducibility of Results; Sensitivity and Specificity; Spectrometry, Mass, Electrospray Ionization

An analytical method for the determination of benazepril and its active metabolite, benazeprilat, in human plasma by capillary gas chromatography-mass-selective detection, with their respective labelled internal standard, was developed and validated according to international regulatory requirements. After addition of the internal standards, the compounds were extracted from plasma by solid-phase extraction using automated 96-well plate technology. After elution, the compounds were converted into their methyl ester derivatives by means of a safe and stable diazomethane derivative. The methyl ester derivatives were determined by gas chromatography using a mass-selective detector at m/z 365 for benazepril and benazeprilat and m/z 370 for the internal standards. Intra- and inter-day accuracy and precision were found to be suitable over the range of concentrations between 2.50 and 1000 ng/mL.

Topics: Benzazepines; Calibration; Gas Chromatography-Mass Spectrometry; Reference Standards; Reproducibility of Results; Sensitivity and Specificity

The disposition and effect of benazepril and its active metabolite, benazeprilat, were evaluated in cats using a pharmacokinetic/pharmacodynamic model. Cats received single 1 mg/kg doses of intravenous 14C-benazeprilat and oral 14C-benazepril.HCl, and single and repeat (eight daily) oral administrations of 0.25, 0.5 and 1.0 mg/kg nonlabelled benazepril.HCl. The pharmacokinetic endpoints were plasma concentrations of benazepril and benazeprilat, and recovery of radioactivity in faeces and urine. The pharmacodynamic endpoint was plasma angiotensin-converting enzyme (ACE) activity. Benazeprilat data were fitted to an equation corresponding to a single-compartment model with a volume equal to the blood space (Vc = 0.093 L/kg). Within this space, benazeprilat was bound nonlinearly to ACE, which was mainly tissular (89.4%) rather than circulating (10.6%). Free benazeprilat was eliminated quickly from the central compartment (t1/2 approximately 1.0 h; Cl approximately 0.125 L/kg/h), elimination being principally biliary ( approximately 85%) rather than urinary ( approximately 15%). Nevertheless, inhibition of ACE was long-lasting (t1/2 16-23 h) due to high affinity binding of benazeprilat to ACE (Kd approximately 3.5 mmol/L, IC50 approximately 4.3 mmol/L). Simulations using the model predict a lack of proportionality between dose of benazepril, plasma benazeprilat concentrations and effect due to the nonlinear binding of benazeprilat to ACE. For example, increasing the dose of benazepril (e.g. above 0.125 mg/kg q24 h) produced only small incremental inhibition of ACE (either peak effect or duration of action).

Topics: Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Animals; Area Under Curve; Benzazepines; Carbon Radioisotopes; Cats; Cross-Over Studies; Dose-Response Relationship, Drug; Feces; Female; Inhibitory Concentration 50; Injections, Intravenous; Male; Models, Biological; Peptidyl-Dipeptidase A

A reversed-phase high-performance liquid chromatographic (HPLC) method was developed and validated for the kinetic investigation of the chemical and enzymatic hydrolysis of benazepril hydrochloride. Kinetic studies on the acidic hydrolysis of benazepril hydrochloride were carried out in 0.1 M hydrochloric acid solution at 50, 53, 58 and 63 degrees C. Benazepril hydrochloride appeared stable in a pH 7.4 phosphate buffered solution at 37 degrees C and showed susceptibility to undergoing in vitro enzymatic hydrolysis with porcine liver esterase (PLE) in a pH 7.4 buffered solution at 37 degrees C. Benazeprilat appeared to be the major degradation product in both (chemical and enzymatic) studies of hydrolysis. Statistical evaluation of the proposed HPLC methods revealed their good linearity and reproducibility. Relative standard deviation (R.S.D.) was less than 4.76, while detection limits for benazepril hydrochloride and benazeprilat were 13.0 x 10(-7) and 9.0 x 10(-7) M, respectively. Treatment of the kinetic data of the acidic hydrolysis was carried out by non-linear regression analysis and k values were determined. The kinetic parameters of the enzymatic hydrolysis were determined by non-linear regression analysis of the data using the equation of Michaelis-Menten.

Topics: Angiotensin-Converting Enzyme Inhibitors; Benzazepines; Carboxylesterase; Carboxylic Ester Hydrolases; Chromatography, High Pressure Liquid; Hydrogen-Ion Concentration; Hydrolysis; Kinetics; Molecular Structure; Prodrugs; Reproducibility of Results

In order to examine the safety of an angiotensin-converting enzyme (ACE) inhibitor in dogs with impaired renal excretion route, benazepril was administered orally, and plasma concentrations of benazeprilat, the active metabolite of benazepril, were determined in dogs with renal mass reduction (1/4th kidney) created by right-side nephrectomy and ligation of branches of the left renal arteries. Five dogs were administered benazepril orally at a given dose (0.5 mg/kg body weight) and 4 other dogs received 20 times that dose (10 mg/kg body weight) once daily for 15 consecutive days before (intact kidney period) and after (1/4th kidney period) creation of kidney impairment. Six control dogs received surgical treatment, but no drug. After creating a 1/4th kidney, plasma urea nitrogen and creatinine concentrations increased to approximately 30 mg/dl and 2.0 mg/dl, respectively, and renal plasma flow and glomerular filtration rate decreased to 37% and 30% of pre-treatment values, respectively. However, these parameters did not change significantly during the 1/4th kidney period both in the 0.5 mg/kg and 10 mg/kg groups. In the 0.5 mg/kg group, plasma benazeprilat concentrations increased to approximately 20 ng/ml to 340 ng/ml 2 hr after each administration, and there were no significant differences between the plasma benazeprilat concentrations during the intact and 1/4th kidney periods. In the 10 mg/kg group, plasma benazeprilat concentrations varied in the individual dog, but did not increase with the days of administration, and were not significantly different on each administration day between the intact and 1/4th kidney periods in either dose group. The AUCs(0-24) of plasma benazeprilat concentrations determined on the 15th administration day were not different between the intact and 1/4th kidney periods in dogs of either dose group. Plasma ACE activities decreased after drug administration in dogs of both groups. Benazepril seemed to have a high safety, and the adjustment of dosage regimen might not be needed in dogs with mild to moderate renal function impairment because the drug was excreted both from the kidneys and liver.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Blood Pressure; Dog Diseases; Dogs; Female; Glomerular Filtration Rate; Kidney Diseases; Male

The plasma pharmacokinetics of benazepril and its active metabolite, benazeprilat, were determined in cats after oral administration of benazepril.HCl at dosages of 0.25, 0.5 and 1.0 mg/kg as a single dose (n = 5 per group) and after once daily application for 8 days (n = 6 per group). Pharmacodynamics were assessed by measurement of plasma angiotensin converting enzyme (ACE) activity. After single administration of benazepril.HCl, maximum benazepril concentrations were recorded at the first sample (2 h) and declined relatively rapidly with an elimination half life (t1/2) of 1.4 h. Highest benazeprilat concentrations were recorded at the first sample (2 h) in most cats and declined biphasically with half lives of each phase of 2.4 and 27.7 h. With repeated administration, plasma benazeprilat concentrations accumulated slightly with accumulation ratios (R) of 1.46, 1.36 and 1.24 for the 0.25, 0.5 and 1.0 mg/kg dosages of benazepril.HCl, respectively (median value of 1.36 for all dosages). All three dosages of benazepril.HCl caused marked inhibition of plasma ACE activity in all cats. The maximum effect (Emax, % inhibition of ACE as compared to baseline) was > or = 98% after single and 100% with repeated administration. The duration of action of benazepril.HCl was long, with > 87% (single) and > 90% (repeat) inhibition of plasma ACE persisting 24 h after dosing. Benazepril.HCl was well tolerated in all animals. Dosages of 0.25-1.0 mg/kg benazepril.HCl once daily are recommended for clinical testing in cats.

Topics: Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Animals; Area Under Curve; Benzazepines; Cats; Drug Administration Schedule; Female; Male; Peptidyl-Dipeptidase A

1. The pharmacokinetics of the angiotensin-converting-enzyme (ACE) inhibitor benazepril were evaluated in eight healthy Beagle dogs. Benazepril was administered orally at a dosage of 7.5 mg (about 0.5 mg/kg) both as a single dose and then once daily for 14 consecutive days. The prodrug, benazepril, and its active metabolite, benazeprilat, were measured in plasma using a gas chromatography mass-spectrometry method with mass-selective detection. 2. Benazepril appeared quickly in the plasma (tmax 0.5 h) and was rapidly eliminated by metabolism to benazeprilat. Peak benazeprilat concentrations were attained later (tmax 1.25 h) and declined biphasically with a rapid elimination phase (t1/2 lambda 1 1.1 and 1.7 h after single and the last repeated dose respectively) followed by a terminal elimination phase (t1/2 lambda z 11.7 and 19.0 h after single and repeated dose respectively). The mean residence time for benazeprilat was 15.2 h after the single dose and 17.4 h after the 14th dose. 3. Repeated administration of benazepril produced moderate bioaccumulation of benazeprilat; the ratio of AUC[0-->24 h]'s after the 14th dose as compared with the single dose was 1.47, equivalent to a half-life for accumulation (t1/2acc) of 14.6 h. Steady-state benazeprilat concentrations at peak (Cmax) and trough (Cmin) were reached within three doses. 4. The pharmacodynamics of benazepril were assessed by measurement of plasma ACE activity. After both single doses and at steady-state, benazepril produced inhibition of ACE activity in all dogs that was maximal at peak effect (Emax = 100%) and long-lasting (> 85% inhibition was present at 24 h). The long duration of action of benazepril on plasma ACE is due to the presence of the terminal elimination phase of benazeprilat, even though most of the metabolite is rapidly eliminated from the plasma.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Dogs; Female; Gas Chromatography-Mass Spectrometry; Kinetics; Male; Peptidyl-Dipeptidase A; Sex Characteristics

Plasma pharmacokinetic variables of benazeprilat, the active metabolite of the angiotensin-converting enzyme (ACE) inhibitor benazepril, were evaluated in healthy Beagles. Benazeprilat was administered IV at a dosage of 0.5 mg/kg of body weight (n = 9). The elimination of half-life of benazeprilat was 3.5 hours, although an additional terminal phase was observed in some dogs. Vehicle (gelatin capsules) or benazepril at dosages of 0.125, 0.25, 0.5, or 1.0 mg/kg was administered orally as a single administration, then once daily for 15 consecutive days (n = 5 or 6/group). Peak benazeprilat concentrations were rapidly attained by 2 hours. Benazeprilat concentrations accumulated moderately with repeated administration, with a peak concentration that was 23% higher and an area under the concentration-time curve that was 34% higher after the 15th dose of benazepril, compared with values after a single dose. The effective half-life for accumulation for all 4 dosages was 12 hours. Steady-state concentrations at 2 hours after administration were achieved after a median (range) of 1 (1 to 6) dose(s). Pharmacodynamic variables were assessed by measurements of plasma ACE activity after oral administration of benazepril or vehicle. All dosages of benazepril caused profound inhibition of ACE, with rapid onset of activity (time to peak effect, 2 hours) and long duration of action (single administration of all 4 doses induced inhibition of ACE that was significantly different from the value in the control [vehicle-treated] dogs for all time points between 1 and 30 hours). Maximal inhibition at all time points was induced by the 0.25-mg/kg dosage at a single administration and with the lowest dosage tested (0.125 mg/kg) at steady state. At steady state, the 0.25-mg/kg dosage caused (mean +/- SEM) 96.9 +/- 2.0% inhibition of ACE activity at maximal effect and 83.6 +/- 4.2% at trough effect (24 hours after dosing), indicating minimal variation in peak/trough effect. Steady-state inhibition of ACE activity at both peak and trough drug effect was achieved after 1 to 4 doses. The data indicate that benazepril is a potent and long-acting ACE inhibitor in dogs.

Topics: Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Animals; Benzazepines; Dogs; Dose-Response Relationship, Drug; Female; Gels; Injections, Intravenous; Male; Peptidyl-Dipeptidase A; Time Factors

We have investigated whether the pharmacokinetics and pharmacodynamics of the ACE inhibitor benazepril hydrochloride are altered with proteinuria by studying 8 patients with major proteinuria of different causes who were given a single dose of 10 mg p.o. The maximum plasma concentration of benazepril was found between 0.5 and 2 h after dosing (median 1 h). Its elimination was almost complete within 6 h. Peak plasma levels of benazeprilat, the active metabolite of benazepril, were observed between 1 and 6 h (median 2.5 h). The elimination of benazeprilat from plasma was biphasic, with mean initial and terminal half-lives of 3.0 and 17.3 h, respectively. On average, the pharmacokinetic parameters of benazepril and benazeprilat in the patients did not differ from those in a historical control group of healthy volunteers, but intersubject variability in the AUC and half-lives of benazeprilat was greater in the patients. Plasma ACE was completely inhibited from 1.5 to 6 h after dosing, and at 48 h the mean inhibition was still 42%. Plasma renin showed substantial intersubject variation. Mean supine blood pressure (systolic/diastolic) was reduced from baseline by a maximum of 18/13 mm Hg at 6 h. Proteinuria was diminished after benazepril in 7 patients. In conclusion, the results of this study suggest that proteinuria in the nephrotic range does not require a change in benazepril dosage.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Benzazepines; Female; Gas Chromatography-Mass Spectrometry; Humans; Male; Middle Aged; Proteinuria

To examine the hemodynamic effects of benazepril, an angiotensin converting enzyme inhibitor, in left ventricular failure, its active metabolite benazeprilat was administered during acute ischemic left ventricular failure in anesthetized open chest dog induced by repeated injections of plastic microspheres into the left coronary artery. The coronary embolization with microspheres resulted in a moderate and stable left ventricular pump failure characterized by increased left ventricular end-diastolic pressure (LVEDP) and decreased cardiac output (CO). Benazeprilat (30 micrograms/kg) administered intravenously after a stabilization period lowered LVEDP and maintained CO. The total peripheral resistance was reduced with benazeprilat. The oxygen consumption and the coronary blood flow were reduced with benazeprilat because of a decrease in wall tension and afterload. These results suggest that benazeprilat (benazepril) has beneficial effects for the treatment of acute left ventricular failure.

Topics: Acute Disease; Animals; Benzazepines; Coronary Disease; Dogs; Heart Failure; Hemodynamics; Microspheres; Ventricular Function, Left

1. The disposition of [14C]-labelled benazepril HCl, an ACE-inhibitor, was studied in four normal adult volunteers after a single oral dose of 20 mg and after repeated doses of 20 mg once daily for 5 days. Radioactivity was measured in plasma, urine and faeces. The prodrug ester benazepril and the pharmacologically active metabolite benazeprilat were determined quantitatively in plasma and urine by a g.c.-m.s. method. The pattern of metabolites in urine was analysed semiquantitatively by h.p.l.c.-radiometry. 2. After a single oral dose at least 37% was absorbed, as indicated by urinary recovery. The peak plasma concentration of benazepril (0.58 +/- 0.13 nmol/g (SD] was observed at 0.5h after dose, indicating rapid absorption. Peak concentrations of radioactivity (1.88 +/- 0.48 nmol/g) and of active benazeprilat (0.84 +/- 0.25 nmol/g) were observed at 1 h after dose, demonstrating rapid bioactivation. 3. The area under the plasma curve (AUC0-96 h) of total radioactivity amounted to 9.7 +/- 1.1 (nmol/g)h, 5% of which was accounted for by benazepril and about 50% by benazeprilat. 4. Over 9 days 96.8 +/- 0.5% of the dose was excreted in urine and faeces. Urinary excretion accounted for 37.0 +/- 6.0% of the dose, 80% of which was recovered in the first 8 h after dosing. 5. In urine, only 0.4% of the dose (1% of the radioactivity) was excreted as unchanged benazepril, indicating that the compound was extensively metabolized. Benazeprilat accounted for 17% of the dose (about half of the radioactivity; 0-96 h). Glucuronide conjugates of benazepril and benazeprilat constituting approximately 11% and 22% of the radioactivity (about 4% and 8% of the dose; 0-48 h) were tentatively identified. 6. Repeated oral treatment with benazepril HCl did not influence the pharmacologically relevant kinetics and disposition parameters.

Topics: Administration, Oral; Adult; Angiotensin-Converting Enzyme Inhibitors; Benzazepines; Blood Proteins; Carbon Radioisotopes; Chromatography, High Pressure Liquid; Feces; Gas Chromatography-Mass Spectrometry; Glucuronates; Half-Life; Humans; Male

The influence of hepatic disease on the pharmacokinetics of the new ACE inhibitor, benazepril hydrochloride, was evaluated in 12 male patients suffering from liver cirrhosis. The patients received a single oral 20 mg dose. The plasma concentrations and urinary excretion of unchanged benazepril and its active metabolite benazeprilat were determined. Compared with a historical control group of healthy volunteers treated with the same benazepril. HC1 dose, the plasma concentrations of benazepril were doubled in the cirrhotic patients. However, the time to reach maximum concentration (0.5 h) was not affected. The plasma kinetics and the urinary excretion of the metabolite benazeprilat were not significantly altered: Area under the curve and maximum concentration as well as time to maximum concentration (1.5 h) were comparable with those in the healthy subjects. There was also no significant difference between the two populations for the total urinary excretion and the renal clearance of benazeprilat. Both benazepril and benazeprilat were highly bound to serum proteins (96 and 94 per cent, respectively). In conclusion, the rate and the amount of bioactivation of the inactive prodrug benazepril to the active benazeprilat were virtually unaffected by hepatic cirrhosis. Thus, there seems to be no need for dosage adjustment of benazepril hydrochloride in patients suffering from cirrhosis of the liver.

Topics: Adult; Aged; Angiotensin-Converting Enzyme Inhibitors; Benzazepines; Blood Proteins; Humans; Liver Cirrhosis; Male; Middle Aged

To investigate the pharmacokinetics of benazepril hydrochloride in special populations, single or multiple doses between 5 and 20 mg of the new drug were given, and the pharmacokinetics of unchanged benazepril and its pharmacologically active metabolite benazeprilat were compared with those in healthy male volunteers. In elderly subjects and patients with mild and moderate renal insufficiency, there was little change in the kinetics of benazepril or benazeprilat. In patients with severe renal impairment (creatinine clearance less than 30 ml/min), benazeprilat elimination was slowed, which resulted in greater accumulation after repeated dosing. In patients with hepatic cirrhosis, the kinetics and bioavailability of benazeprilat were not affected. Therefore dose adjustment is unnecessary because of the patient's age, mild or moderate renal impairment, or hepatic cirrhosis. Dose reduction is necessary in patients with creatinine clearance less than 30 ml/min.

Topics: Aged; Aged, 80 and over; Benzazepines; Dose-Response Relationship, Drug; Female; Humans; Kidney Failure, Chronic; Kidney Function Tests; Liver Cirrhosis; Male; Metabolic Clearance Rate

The present study investigated the effect of the angiotensin-converting enzyme (ACE) inhibitors, captopril, CGS14824A and CGS14831 on in vitro rat aortic and urinary bladder prostacyclin (PGI2; measured as 6-oxo-PGF1 alpha by radioimmunoassay) synthesis. PGI2 synthesis was stimulated with adrenaline (aorta), carbachol (bladder), calcium ionophore A23187, arachidonate and trauma. The ACE inhibitors antagonised adrenaline-, carbachol- and A23187-stimulated PGI2 synthesis in the aorta and bladder (CGS14824A greater than captopril greater than CGS14831) but were without effect on trauma- or arachidonate-stimulated PGI2 synthesis. The patterns of inhibition of these ACE inhibitors, using the same stimulatory regimes, was very similar to those previously observed by us with known calcium channel blockers (nifedipine, verapamil). These data suggest that: (i) ACE inhibitors possess calcium channel blocking properties, which may be of relevance to the antihypertensive action of these drugs; and (ii) ACE inhibitors did not stimulate vascular PGI2 synthesis as has been previously suggested.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Arachidonic Acid; Arachidonic Acids; Benzazepines; Calcimycin; Calcium Channel Blockers; Captopril; Carbachol; Epinephrine; Epoprostenol; In Vitro Techniques; Male; Muscle, Smooth; Muscle, Smooth, Vascular; Rats; Rats, Inbred Strains; Urinary Bladder; Wounds and Injuries

Topics: Angiotensin-Converting Enzyme Inhibitors; Benzazepines; Chemical Phenomena; Chemistry; Gas Chromatography-Mass Spectrometry; Humans