Doris N. McKinstry

Antihypertensive Effect of the Oral Angiotensin Converting-Enzyme Inhibitor Sq 14225 in Man

We investigated the antihypertensive effect of the angiotensin converting-enzyme inhibitor SQ 14225 in 12 hypertensive patients for periods of three to 24 weeks. Blood pressure decreased in all patients (from 177 +/- 8/110 +/- 2 to 136 +/- 6/88 +/- 2 mm Hg--mean +/- S.E.); oral doses ranged from 400 to 1000 mg daily. Concomitant effects noted were small increases in plasma potassium concentration and pulse rate. One patient experienced a transient febrile reaction. Plasma renin activity rose during treatment, plasma aldosterone decreased, and angiotensin-converting-enzyme activity was virtually eliminated. There was no significant correlation between pretreatment plasma renin activity and degree of blood-pressure fall with SQ 14225. The exact mechanisms contributing to the blood-pressure-lowering effect of this agent remain unclear. SQ 14225 is a promising new antihypertensive agent, effective in patients refractory to traditional medical therapy.

Disposition of captopril in normal subjects

The disposition of Captopril, an angiotensin‐converting enzyme inhibitor with antihypertensive properties, was studied in 10 normal male subjects after a single 100‐mg tablet of 35S‐labeled drug. Average absorption parameters for unchanged Captopril in blood were Tmax 0.93 ± 0.08 hr and Cmax 800 ± 76 ng/ml. For total radioactivity in blood the values were Tmax 1.05 ± 0.08 hr and Cmax 1,580 ± 90 ng/ml (as Captopril equivalents). Because of the curvilinearity of the semilogarithmic plots of blood concentrations of Captopril: time, elimination half‐life (t½) of unchanged drug could not be determined. At 1 hr unchanged Captopril accounted for about 52% of total radioactivity in blood, and the dimeric disulfide metabolite of Captopril accounted for about 10%. In the first 5 days after dosing, an average of about 68% of the radioactive dose was recovered in urine and 18% in feces. The distribution of radioactivity in the first 24‐hr urine sample (66% of the dose) was 58% Captopril (38% of dose), 2% Captopril disulfide (1.5% of dose), and 40% unidentified polar metabolites (26% of dose).

Renal handling of captopril: Effect of probenecid

14C‐Captopril was given intravenously to four normal subjects in a 4‐mg priming dose followed by constant intravenous infusion of 1.7 mg/hr for 3.5 hr with and without concomitant probenecid. Steady‐state levels of unchanged captopril were obtained between 1.5 and 3.5 hr. In the presence of probenecid, the average steady‐state blood levels of total radioactivity were higher (36%) than on captopril alone. Unchanged captopril levels were slightly higher (14%) in the presence of probenecid. Kinetic evaluations were carried out exclusively on data for unchanged captopril. The average total body clearance (ClT) and renal clearance (ClR) of captopril in the absence of probenecid were 775 and 388 ml/kg/hr. The corresponding values for captopril with probenecid (631 and 217 ml/kg/hr) were lower. The average ratio of ClR to ClT for captopril alone was 0.50 and fell to 0.35 in the presence of probenecid. When captopril alone was given, a minimum of 78% of the renal excretion of captopril during steady‐state could be attributed to net tubular secretion, but when captopril was given with probenecid, net tubular secretion was only 57%. The volume of distribution of captopril during steady state was not altered by probenecid. For the first 3.5 hr, cumulative renal excretion of total radioactivity with and without probenecid was 55% and 60%, but cumulative excretion of unchanged captopril was higher after captopril alone (36% of dose) than after the combination (21% of dose).

Pharmacokinetics of Captopril in Elderly Healthy Male Volunteers

The pharmacokinetics of captopril were studied in 12 healthy male volunteers aged 65 to 76 years, who each received a single 100‐mg oral dose. Blood and urine samples were collected over a 24‐hour period, and assayed for unchanged captopril (CAP), S‐methyl captopril (Me‐CAP, plasma concentrations from 2 subjects only), and total captopril levels (TOT, a mixture of CAP and its dimer and mixed disulfides with endogenous thiolcontaining compounds such as glutathione and cysteine). Mean values for the maximum concentration (Cmax) were 803 and 66.3 ng/mL for CAP and Me‐CAP, respectively. Mean time to maximum concentration (tmax) was determined as 1.0, 1.4, and 1.0 for CAP, TOT, and Me‐CAP, respectively. Mean areas under the plasma concentration‐time curve (AUC) were 1,394 hr‐ng/mL (CAP, 0–8 hr) and 17,316 hr‐ng/mL (TOT, 0–24 hr). The mean estimated half‐life (t1/2) for CAP was 1.4 hr, and its renal clearance was 187 mL/hr/kg. Mean urinary excretion over 24 hr was 20.8 and 53.1 for CAP and TOT, respectively. Cmax, and AUC for CAP were 9% less and 13% greater, respectively, than in a historical control group of 18–35‐year‐old men, treated in the same clinic, by the same personnel, using the same analytic procedures, whereas the 24‐hour urinary excretion was 25% lower and eight‐hour renal clearance 36% lower in the older population. Since the values for Cmax, AUC, and t1/2 were similar in the two populations, it does not appear that the pharmacokinetics of CAP are altered markedly with age alone.

Comparison of kinetic interactions of nadolol and propranolol with cimetidine

Plasma levels of nadolol and propranolol following a single 80 mg dose of each beta blocker in the presence and absence of cimetidine were determined in 12 healthy male subjects. Cimetidine increased (p less than 0.01) the area under the plasma concentration-time curve and peak plasma levels of propranolol by 46% and 35%, respectively. Nadolol kinetics were not altered significantly by cimetidine, except for a reduction in time to reach peak concentrations. The higher blood levels of propranolol during administration of cimetidine were not associated with any changes in resting blood pressure or heart rate compared with propranolol alone. Cimetidine had no effect on elimination half-lives or apparent mean residence times for either beta blocker.