Pharmacokinetics of ramipril in hypertensive patients with renal insufficiency.

In an open trial, the pharmacokinetics of ramipril and its active metabolite ramiprilat were studied in 25 hypertensive patients with various degrees of renal insufficiency given 5 mg ramipril p.o. for 14 days. Ramipril was rapidly absorbed and reached a peak concentration after 1-2 h. Cmax was greater in patients with severe renal insufficiency, which might indicate a reduced renal elimination rate, although, the rapid decline of the concentration-time curve for ramipril was almost independent of renal function. The mean initial apparent half-lives on Days 1 and 12, respectively, were 2.8 and 3.4 h (Group I: creatinine clearance 5-15 ml/min), 1.8 and 2.3 h (Group II: creatinine clearance 15-40 ml/min), and 1.9 and 1.9 h (Group III: creatinine clearance 40-80 ml/min). No accumulation was observed after multiple dosing. In contrast, the kinetics of its active acid metabolite ramiprilat was significantly influenced by renal function. The mean times to the peak plasma concentration were 5.7 h in Group I, 4.4 h in Group II and 3.8 h in Group III. The initial decline in plasma ramiprilat was dependent upon renal function; the mean initial apparent half-lives (Days 1 and 12, respectively) were 16.0 and 14.8 h (Group I), 10.1 and 9.5 h (Group II) and 10.6 and 8.0 h (Group III). Mean trough concentrations and absolute accumulation also increased with worsening renal function, and the renal clearance of ramiprilat was significantly correlated with the creatinine clearance. The subsequent long terminal phase at low plasma ramiprilat concentrations represented slow dissociation of the ACE-inhibitor complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacodynamic effects of a single 10-mg dose of the angiotensin converting enzyme inhibitor ramipril in patients with impaired renal function.

A single oral 10-mg dose of ramipril, a long-acting angiotensin converting enzyme (ACE) inhibitor, was given to 24 hypertensive patients with different degrees of renal function. Creatinine clearance ranged from below 15 ml/min (n = 9) to above 80 ml/min (n = 3). Serial blood samples were taken for the determination of ACE activity, plasma renin activity (PRA), aldosterone (ALDO), angiotensin II (AT II), and serum creatinine (CR). Blood pressure was also monitored before and after medication. After administration of ramipril systolic and diastolic blood pressure (BP) fell; the decreases were unrelated to renal function. Peak BP-lowering effect was seen at 6 h basal, 174 +/- 19.5/102.6 +/- 8.9 to 149.8 +/- 19.7/87.6 +/- 13.3 mm Hg (mean +/- SD; p less than 0.001). ACE inhibition occurred within 2 h, being maximal at 4 h: basal, 82.6 +/- 17.9 to 0.2 +/- 0.6 nmol/ml/min (p less than 0.001). The greater the renal impairment, the longer the ACE inhibition. Angiotensin II was reduced maximally at 10 h after dosing, from 10.4 +/- 5.4 to 6.2 +/- 3.6 pg/ml (p less than 0.01). Aldosterone also fell from 212 +/- 188.4 to 134 +/- 73.3 pg/ml at 6 h (p less than 0.01). Plasma creatinine was unchanged: 401.3 +/- 315.7 to 394.9 +/- 306.1 nmol/L (NS). Ramipril, given as a single oral dose, lowers BP in hypertensives with both normal and impaired renal function, inhibits ACE activity, and causes no change in serum creatinine.

Pharmacokinetic and pharmacodynamic properties of ramipril in patients with congestive heart failure (NYHA III-IV).

To investigate the pharmacokinetics and pharmacodynamics of a new angiotensin converting enzyme (ACE) inhibitor, ramipril (HOE 498), in patients with cardiac insufficiency (NYHA III-IV), we performed an open trial with a follow-up of 10 days. Twenty-seven patients (18 females, 9 males), mean aged 62 years (46-83) with severe heart failure, were included. After a single oral dose of 5 mg ramipril, the plasma and urine levels of ramipril, ramiprilat, ACE plasma activity, standard laboratory values, blood pressure and pulse rate were evaluated. The maximal plasma level of ramipril was 57.0 +/- 26.8 ng/ml after 1.4 h; t1/2 was 2.4 +/- 1.2 h. The peak level of ramiprilat was 27.9 +/- 24 ng/ml after 4.6 h; t1/2 for the active compound was 6 +/- 4.2 h. The total recovery of ramipril and metabolites in urine was on average 39 +/- 17.5% within 96 h. Ninety-five percent inhibition of ACE activity was observed in all patients and 80% inhibition lasted 24 h. Systolic and diastolic blood pressure decreased without changes in heart rate. Five patients had mild side effects: hypotension, diarrhea, and dizziness. In conclusion, in patients with severe heart failure, plasma levels of drug and active metabolite were higher and remained measurable longer, with more sustained inhibition of ACE activity than reported in healthy volunteers. This indicates that titration should start with lower doses (1.25-2.5 mg) and that doses above 5 mg may rarely be necessary.

Steady-state kinetics of ramipril in renal failure.

In an open trial, the pharmacokinetics of ramipril and its active metabolite ramiprilat were studied in 23 hypertensive patients with various degrees of renal insufficiency. During a 2-week treatment period, each subject took daily a 5-mg tablet of ramipril. Serum profiles and urinary excretion of the parent compound and ramiprilat, the active metabolite, were then evaluated. Peak concentrations of ramipril were slightly greater in patients with severe renal insufficiency; however, most of the ramipril was metabolized in the liver. The drug concentration-time curve was almost independent of renal function and no accumulation was observed after multiple dosing. In contrast, ramiprilat kinetics were significantly influenced by renal function. Initial apparent half-lives (8-16 h), mean trough concentrations (5-19 ng/ml), and absolute accumulation all increased with worsening renal function, and renal clearance of ramiprilat was significantly correlated with creatinine clearance. The subsequent long terminal phase at low ramiprilat serum concentration represents the slow dissociation of the angiotensin converting enzyme (ACE)-bound drug. This study indicates that in patients with severe renal insufficiency (creatinine clearance below 30 ml/min), smaller doses of ramipril will be required than in patients with normal or borderline normal renal function.

Therapeutic efficacy and tolerance of ramipril in hypertensive patients with renal failure.

In an open trial, the antihypertensive and hormonal effects of ramipril, a new nonsulfhydryl angiotensin converting enzyme (ACE) inhibitor, were studied in 23 hypertensive patients with various degrees of renal failure: group I, creatinine clearance 5-15 ml/min, n = 10; group II, creatinine clearance 15-40 ml/min, n = 7; group III, creatinine clearance 40-80 ml/min, n = 6. In a 2-week placebo run-in period, antihypertensive agents were reduced or discontinued. During the treatment phase, patients received a 5-mg tablet of ramipril once daily for a period of 2 weeks. Concomitant medication remained unchanged. In all groups, ramipril significantly decreased mean arterial blood pressure. Blood pressure response was not different in the three groups, although plasma ramipril levels were higher in patients with severe renal failure. In patients with high plasma renin activity (PRA), reduction of blood pressure was greater than in subjects with low PRA. Plasma ACE activity was suppressed to less than 20% of its initial value in all groups during the whole treatment period, and the suppression was more marked and lasted longer in patients with severe renal failure. A strong correlation between the plasma ramiprilat levels and the inhibition of plasma ACE activity was noted for all groups. Mean serum creatinine did not increase significantly; serum potassium levels rose from 4.5 to 4.9 mmol/L on day 14 (p less than 0.01). In conclusion, in patients with various degrees of renal failure, ramipril represents an effective and well-tolerated antihypertensive agent.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of ramipril in the elderly.

Ramipril (HOE 498) is a pro-drug of which the main metabolite (HOE 498 diacid or ramiprilat) is a potent angiotensin converting enzyme inhibitor. Thirteen healthy white volunteers (5 females and 8 males, ages 65 to 76 years) participated in a study to investigate the pharmacokinetics of HOE 498 in the elderly. After administration of 10 mg of HOE 498, sequential urine and serum specimens were obtained for assay of HOE 498 and metabolites (HOE 498-glucuronide, diacid, diacid-glucuronide, diketopiperazine and diketopiperazine acid). Side effects, clinical chemistry and hematology were monitored. HOE 498 reached peak concentrations of 62.4 +/- 23.3 ng/ml in serum after 0.7 +/- 0.3 hours. Serum levels decreased with an apparent half-life of 0.9 +/- 0.4 hours. The diacid was rapidly formed in serum, reaching peak concentrations of 40.6 +/- 14.0 ng/ml after 2.0 +/- 0.6 hours and declining with a half-life of 2.2 +/- 0.5 hours. A prolonged terminal phase of serum concentration versus time curve was observed at concentrations less than 1 ng/ml. The mean recovery of HOE 498 and metabolites in urine, up to 26 hours after administration, was 35 +/- 14% of the dose. The apparent half-lives, calculated from urine parameters, for HOE 498 and the diacid were 2.6 +/- 0.9 and 4.0 +/- 1.1 hours, respectively. The mean peak concentration and half-life of HOE 498 in serum are slightly higher in the elderly than in younger volunteers. Complete urinary collection was not possible, but urinary recovery did not seem different from younger volunteers.

Pharmacokinetic interaction study with ramipril and digoxin in healthy volunteers.

Coadministration of captopril has been shown to increase serum digoxin concentration. The effects of ramipril, a new angiotensin converting enzyme inhibitor, on serum digoxin concentration after multiple dosing were studied in 12 healthy volunteers. All subjects were receiving steady-state digoxin medication (0.5 mg daily), and ramipril (5 mg daily) was coadministered for 14 days. Serum digoxin concentration was measured repeatedly before, during and up to 1 week after ramipril coadministration at 8 a.m. (trough values) and on selected trial days at 11 a.m., 3 hours after the morning medication. Simultaneously, blood levels of ramipril and its active metabolite diacid were determined. Volunteers were followed closely for side effects and for changes in blood pressure, heart rate and electrocardiogram. Safety pharmacology included serial determination of sodium, potassium, serum glutamic oxaloacetic transaminase, creatinine and a full blood count. Mean serum digoxin concentration was not significantly influenced by ramipril coadministration with trough levels of 0.90 +/- 0.24 before, 0.93 +/- 0.38 during and 0.82 +/- 0.33 ng/ml after ramipril medication. The increase in serum digoxin concentration 3 hours after the morning dose was also not significantly affected by ramipril. Serum levels of ramipril and its diacid showed a wide range of variation. Mean serum potassium increased by 0.3 mmol/liter during ramipril coadministration with development of symptomless hyperkalemia (6.0 mmol/liter) in 1 subject. The only other side effect possibly related to ramipril was a dry cough in 1 subject. Both drugs were well tolerated. Ramipril showed no significant influence on serum digoxin levels in healthy volunteers.

Pharmacokinetics and pharmacodynamics of ramipril in renal failure.

The pharmacokinetics and pharmacodynamics of the novel angiotensin converting enzyme (ACE) inhibitor ramipril were studied in 6 patients with a glomerular filtration rate of less than 20 ml/min/1.73 m2 of body surface area. A single oral dose of 5 mg was given and serum concentrations of the compound and its diacid, the active metabolite (ramiprilat), as well as ACE activity, blood pressure and pulse rate were monitored for 28 days. The original compound reached peak serum concentrations of 42.8 +/- 26.5 ng/ml about 1 hour after dosing and was completely eliminated from the serum after 24 hours. Ramiprilat reached peak values of 14.4 +/- 11.6 ng/ml after about 6 hours. In contrast with the parent compound, low concentrations of ramiprilat were still detected in the serum after 28 days. ACE activity decreased to approximately 5% of baseline values, remained low for the next 48 hours, then increased slowly thereafter but reached only 84.5% of initial values after 28 days. Blood pressure decreased significantly and remained low for 24 hours after dosing. The drug was well tolerated in all patients. It is concluded that a single 5 mg dose of ramipril was effective in inhibiting plasma ACE activity and lowering blood pressure in patients with renal failure. There was a slower decline in ramiprilat concentrations compared with subjects with normal renal function.

Influence of renal function on the pharmacokinetics of ramipril (HOE 498).

The pharmacokinetics of ramipril (HOE 498) were studied after oral administration of a single 10 mg dose to 24 hypertensive patients with different degrees of renal function. The creatinine clearance ranged between 4.1 and 126 ml/min/1.73 m2 and was below 35 ml/min/1.73 m2 in 16 patients. Angiotensin converting enzyme activity and the concentrations of ramipril and its active diacid metabolite ramiprilat were measured in plasma up to 10 days after drug intake. Urine levels of ramipril, ramiprilat, their glucuronides and 2 major metabolites (a diketopiperazine and a diketopiperazine acid) were measured up to 4 days after medication. The plasma concentration-time curve of ramiprilat was polyphasic with an initial steep decline after the peak level and a subsequent very long terminal phase at low concentrations. Impaired renal function resulted in higher peak levels of ramiprilat, longer times to peak and a markedly slower decline of plasma ramiprilat levels. Hence, the duration of angiotensin converting enzyme inhibition was considerably prolonged in renal failure and depended on the severity of renal impairment. The urinary excretion of ramipril and its metabolites decreased with decreasing renal function and was linearly related to the creatinine clearance, suggesting an alternative pathway of elimination. The pattern of excretion rates of ramipril and its various metabolites was not affected by renal failure. In contrast to the marked changes in the renal elimination, no relevant differences were observed in the absorption of ramipril from the gastrointestinal tract. Systolic and diastolic blood pressure decreased in all groups. The single 10 mg dose of ramipril was well tolerated.

Lack of effect of piretanide (a potassium-stable diuretic) on serum magnesium.

Serum magnesium and potassium concentrations were determined in 188 patients undergoing diuretic treatment for mild to moderate hypertension in four controlled clinical trials (eleven treatment groups). Measurements were made before and after 12 weeks of treatment with piretanide monosubstance (including the retarded form) in the range 3 to 12 mg daily, with triamterene as monosubstance and in fixed dose combination with piretanide, and with amiloride in combination with hydrochlorothiazide. Eumagnesaemia and eupotassaemia were preserved at all dosage of the piretanide monosubstance. Mean serum potassium concentrations were significantly increased following treatment with the potassium-sparing agents triamterene (with and without piretanide) and amiloride in combination with hydrochlorothiazide. These changes were not accompanied by changes in mean serum magnesium levels, that is, a magnesium-sparing effect was not demonstrated. Individual values of changes in serum magnesium levels before and after diuretic therapy did not correlate with the corresponding changes in serum potassium levels in any of the eleven groups of patients. This result is in contrast to the findings of other authors, which suggested that serum magnesium and potassium levels were correlated. Long-term treatment with diuretics can lead to hypomagnesaemia and hypokalaemia, and, if in combination with a potassium-sparer, to hyperkalaemia. The results of this analysis show that piretanide, in addition to its smooth and effective antihypertensive action, is also able to preserve serum magnesium and potassium homeostasis when administered in the range of 3 to 12 mg for 12 weeks.

Humoral and blood pressure effects of the angiotensin converting enzyme inhibitor ramipril in essential hypertension.

The humoral and antihypertensive activities of the angiotensin converting enzyme (ACE) inhibitor 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S, 3S, 5S)-2-azabicyclo[3.3.0] octane-3-carboxylic acid (ramipril, Hoe 498) were investigated in 10 patients with essential hypertension (WHO stage I or II). After a 7-day placebo period, the patients were treated with 5 mg ramipril orally once daily for 14 days. Peak serum concentrations of the active metabolite M1 (dicarboxylic acid) of 5.4-62.0 ng/ml were observed 2-6 h after the first oral dose. The maximum ACE inhibition of 95% was reached 2-4 h after the first oral dose, inhibition exceeded 70% 24 h after dosing. The maximum drop in the systolic and diastolic blood pressure (random zero sphygmomanometer) was measured 4 h after ramipril (p less than 0.02, p less than 0.01), but blood pressure on days 7 and 14 of the treatment period was not different from pretreatment values. Automatically recorded blood pressure results showed a marked reduction of both systolic and diastolic blood pressure during treatment compared to placebo. No side effects occurred. From the present data it is concluded that ramipril is a potent ACE inhibitor in hypertensive patients and that further controlled studies are required for the evaluation of the antihypertensive effect of 5 mg ramipril in essential hypertension.

Pharmacokinetics of pheniramine (Avil) and metabolites in healthy subjects after oral and intravenous administration.

The pharmacokinetics of pheniramine and its two metabolites (N-desmethyl pheniramine and N-didesmethyl pheniramine) were determined in six healthy male subjects after intravenous (n = 3) or oral (n = 3) administration (30.5 mg of pheniramine - free base). Serum and urine levels were measured by HPLC. After i.v. administration, serum concentrations of pheniramine between 231 and 894 ng/ml were reached and after oral administration peak serum concentrations between 173 and 274 ng/ml were reached after 1-2.5 h. AUC values up to 72 h were 3035-4662 (i.v.) and 3507-5768 (ng/ml X h) (oral). The terminal half-lives were estimated to range between 8 and 17 h (i.v.) and 16 and 19 h (oral). Serum levels of the N-desmethyl derivative remained very low (up to 21 ng/ml), but were still detectable after 72 h. Serum levels of the N-didesmethyl derivative were below the detection limit. The amount of pheniramine excreted in the urine for up to 120 h varied between 5.7 and 11.6 mg and 10.2 and 13.2 mg after i.v. and oral administration respectively. Unlike the serum, considerable fractions of the drug occurred as metabolites in urine. Values were 8.1-16.4 mg (i.v.) and 7.4-13.3 mg (oral) for N-desmethyl pheniramine, 0.4-2.9 mg (i.v.) and 0.2-0.8 mg (oral) for N-didesmethyl pheniramine.

Tolerance and pharmacodynamics of the angiotensin converting enzyme inhibitor 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S,5S)-2- azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) in healthy volunteers.

In healthy volunteers a single oral dose of 5 mg 2-[N-[(S)-1-Ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S, 5S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid (Hoe 498) was well tolerated. Following 5 mg Hoe 498 plasma angiotensin converting enzyme (ACE) activity was inhibited by almost 100% up to 8 h. A marked effect on plasma ACE was observed for more than 8 days. Plasma renin activity increased whereas aldosterone plasma levels decreased only slightly. Sodium and potassium excretion was not influenced by the compound. Systolic and diastolic blood pressure was slightly lowered by Hoe 498, whereas no relevant changes in pulse rate were observed.

Pharmacokinetics and pharmacodynamics of a novel orally active angiotensin converting enzyme inhibitor (HOE 498) in healthy subjects.

The pharmacokinetics and pharmacodynamics of the angiotensin converting enzyme inhibitor HOE 498 were investigated in 10 healthy normotensive male subjects. Serum levels of the active metabolite M 1 (dicarboxylic acid) of HOE 498 were measured by HPLC up to 14 days after a single oral dose of 10 mg HOE 498. Peak serum concentration of M 1 between 5-50 ng/ml was observed 1.5-3.0 h after administration. The serum concentration-time curve of M 1 was polyphasic and exhibited a prolonged terminal phase with a half-life of approximately 110 h. Despite the long terminal half-life M 1 could not be detected in urine later than 72 h after administration. The activity of the angiotensin converting enzyme in plasma was completely suppressed for up to 12 h, and 72 h after dosing 50% inhibition of the enzyme was still observed.

A radioimmunoassay to measure piretanide in human serum and urine.

This paper describes a specific radioimmunological method for determining the diuretic agent piretanide (4 phenoxy-3-(1-pyrrolidinyl)-5-sulfamoyl benzoic acid) in human serum, plasma and urine. The antiserum was raised in rabbits against an immunogen of piretanide coupled to bovine serum albumin. The iodinated hydroxy derivative of piretanide was used as tracer. The separation of free and antibody-bound piretanide was performed by precipitating the antibody-tracer complex by polyethylene glycol. The limit of detection was 4 ng/ml. Studies on specificity showed less than 0.5% cross-reactivity of an identified metabolite. Interassay reproducibility showed an average coefficient of variation of 7.3%, the interassay variation was 5%. A recovery experiment yielded 100.9% recovery. There is good agreement between parallel determinations of piretanide by RIA and HPLC in both human serum and urine.

A radioimmunoassay for determination of glibenclamide and other sulfonylureas.

An antiserum was prepared for the determination of glibenclamide and for the estimation of other commercially available sulfonylureas. Rabbits were immunized with a glibenclamide-BSA conjugate. Tritiated glibenclamide was used as the tracer. The assay was performed in the presence of 8-anilinonaphthalenesulfonic acid to displace glibenclamide bound to serum protein, and free and antibody bound tracer were separated by dextran-coated charcoal. For glibenclamide determination in serum and plasma the limit of detection was 3 ng/ml. Sensitivity calculated for the whole determination range was 102 cpm for a 10 % concentration difference. Specificity studies showed a cross-reaction of less than 0.1 % for glibenclamide metabolite M1 and 9 % for metabolite M2. Other sulfonylurea drugs display cross-reactivities from 0.1% (chlorpropamide) to 190% (gliquidone). Both intra-assay and inter-assay imprecision were below 10 %. Accuracy was established by comparison of the present method with HPLC. The assay was applied to the specific determination of glibenclamide in clinical trials and for diagnosing factitious hypoglycemia caused by sulfonylureas.