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Biomedical subjects

K L Duchin

Publications and source records attributed to K L Duchin.

At least 19 recordsLinked to original sources
PubMed1996

Bioequivalence of a highly variable drug: an experience with nadolol.

PURPOSE: To assess the bioequivalence of nadolol 40mg and 160mg tablets (Zenith-Goldline Pharmaceuticals) using Corgard 40mg and 160mg tablets (Bristol-Meyers Squibb) as reference products, to estimate the effect of food in the gastrointestinal tract on nadolol bioavailability, and to evaluate the effectiveness of standard pharmacokinetic metrics AUCt, AUC infinity, and Cmax in bioequivalence determinations. METHODS: Four bioequivalence studies were conducted as described in the FDA Guidance. Four additional studies of varying designs were conducted to establish bioequivalence of the 40mg tablet in terms of Cmax. RESULTS: Fasted and food-effect studies of the 160mg tablet clearly established bioequivalence and revealed an unexpected reduction in nadolol bioavailability from test and reference products in the presence of food. The food-effect study of the 40mg tablet (80mg dose) revealed a similar reduction in bioavailability from each product. Fasted studies of the 40mg tablet (80mg dose) established bioequivalence in terms of AUCt and AUC infinity. However, Cmax criteria proved extremely difficult to meet in the initial 40mg fasted study because of the large variability, leading to additional studies and ultimately requiring an unreasonable number of subjects. CONCLUSIONS: Final results clearly established bioequivalence of both strengths and characterized an unexpected food effect which did not appear to be formulation-related. However, the Cmax of nadolol is only slightly sensitive to absorption rate and the relatively large variability of Cmax reduces its effectiveness as a bioequivalence metric. Findings suggest that bioequivalence criteria for highly variable drugs should be reconsidered.

Administration, Oral↗
PubMed1993

The pharmacokinetics and pharmacodynamics of fosinopril in haemodialysis patients.

The pharmacokinetics and pharmacodynamics of fosinoprilat, the diacid of fosinopril sodium (a new angiotensin-converting enzyme (ACE) inhibitor), were investigated in six haemodialysis patients. Intravenous 14C-fosinoprilat (7.5 mg), oral 14C-fosinopril sodium (10 mg) and oral fosinopril sodium (10 mg) were administered in an open-label, randomized study. Mean maximum concentration (Cmax), clearance (CL), volume of distribution at steady-state (Vss), mean residence time (MRTiv), and t1/2 values after IV administration of 14C-fosinoprilat were 2,042 micrograms.ml-1, 11.3 ml.min-1, 11.0 l, 16.3 h and 28.3 h, respectively. Following oral administration of 14C-fosinopril, mean Cmax, time to maximum plasma concentration (tmax), and fosinoprilat bioavailability values were 197 ng.ml-1, 5.2 h and 29.2%. Para-hydroxy fosinoprilat and fosinoprilat glucuronide comprised approximately 15% and 2% of radioactivity recovered in faeces. Four hours of haemodialysis only cleared approximately 1.5% of the administered dose. The maximum effect (Emax) model was fitted to the percentage inhibition of serum ACE activity vs. fosinoprilat concentration data in three patients. Emax ranged from 95.3 to 102.5%, and IC50 (the fosinoprilat concentration required to produce 50% of Emax) ranged from 2.6 to 4.2 ng.ml-1. Pharmacokinetic variables of the patients were similar to those in patients with moderate to severe renal dysfunction. Dosage modifications or supplemental dosing following dialysis are unnecessary.

Administration, Oral↗
PubMed1991

Pharmacokinetics, safety, and pharmacologic effects of fosinopril sodium, an angiotensin-converting enzyme inhibitor in healthy subjects.

The pharmacokinetics, pharmacodynamics, and safety of fosinopril sodium (SQ 28,555), a new orally active angiotensin-converting enzyme (ACE) inhibitor, was evaluated in 73 healthy men in two separate studies. In study I, doses ranging from 10 to 640 mg were administered once daily for 3 days to seven groups of five subjects each. Serum aldosterone levels, ACE activity, and sitting blood pressure were determined, as were pharmacokinetic parameters of fosinoprilat, the active diacid of fosinopril. In a dose-tolerance study (study II), 80 and 160 mg of the drug were administered in doses of 40 mg bid and 80 mg bid for 2 weeks. Pharmacokinetics were determined on days 1 and 14, and blood pressure and ACE activity were measured daily. One hour after all doses of fosinopril, serum ACE activity was undetectable. Peak blood levels of fosinoprilat occurred at about 3 hours after dosing, and linear kinetics of the diacid were observed. ACE activity remained undetectable for more than 24 hours after the treatment was stopped in study II. Serum aldosterone levels were decreased by 50% of baseline values in both studies. In study I, maximal reductions in mean blood pressure occurred approximately 6 hours postdose; once-daily doses of 20 mg or greater achieved reductions of 11.3 to 21.6% (P less than or equal to .05, compared with placebo reductions). Fosinopril was well tolerated. Subjects reported only mild gastrointestinal complications at doses of 80 mg/day or higher. These data show that fosinopril is a safe and effective inhibitor of ACE with a long duration of action on serum ACE activity.

Adolescent↗
PubMed1991

Fosinopril pharmacokinetics and pharmacodynamics in chronic ambulatory peritoneal dialysis patients.

The pharmacokinetics and pharmacodynamics of fosinoprilat, the diacid of fosinopril sodium, a new angiotensin-converting enzyme (ACE) inhibitor, were investigated after the oral administration of 10 mg of fosinopril sodium to 6 chronic ambulatory peritoneal dialysis (CAPD) patients. The results from 1 patient are reported separately because of the presence of concomitant liver dysfunction. The mean t1/2, Cmax, tmax, and AUC values for 5 of the CAPD patients were 19.5 h, 202 ng.ml-1, 4.8 h, and 3.19 micrograms.h.ml-1, respectively. Values for 1 CAPD patient with liver dysfunction were t1/2 of 65.4 h, Cmax of 182 ng.ml-1, tmax of 9 h, and AUC of 18.1 micrograms.h.ml-1. Peritoneal clearance of fosinoprilat was negligible, ranging from 0.07 to 0.23 ml.min-1. Serum ACE activity remained significantly suppressed at 24 and 48 h after fosinopril sodium administration with mean decreases from baseline of 94.2% and 70.6%, respectively. ACE activity was suppressed to an even greater degree in the patient with liver dysfunction, remaining 97% inhibited 72 h after drug administration. Plasma renin activity (PRA) increased and plasma aldosterone concentrations decreased following drug administration. Mean arterial pressure did not change appreciably throughout the study. Dosage reductions may not be necessary in the majority of dialysis patients.

Adult↗
PubMed1991

Pharmacokinetics of fosinopril in patients with various degrees of renal function.

Single-dose kinetics of fosinopril, a new phosphorus-containing angiotensin-converting enzyme inhibitor and its active diacid, fosinoprilat, were investigated in patients with mild, moderate, or severe renal impairment and in those with normal renal function. After an intravenous dose of 14C-fosinoprilat (7.5 mg), total body clearance of fosinoprilat was significantly greater (p less than 0.05) in patients with normal renal function than in renally impaired patients but was not related to the degree of renal impairment in patients with creatinine clearance values of 11 to 72 ml/min/1.73 m2. Decreases in renal clearance were compensated for by increases in hepatic clearance, so that total clearance was maintained. After oral 14C-fosinopril (10 mg), plasma kinetics and bioavailability of fosinoprilat were similar for the three groups of renally impaired patients. The dual elimination of fosinoprilat by the liver and the kidney distinguishes fosinopril from other angiotensin-converting enzyme inhibitors.

Administration, Oral↗
PubMed1991

Once-daily fosinopril in the treatment of hypertension.

This multicenter, dose-ranging study evaluated the antihypertensive effectiveness of once-daily administration of fosinopril sodium in 220 patients with supine diastolic blood pressure of 95-115 mm Hg. After a 4-week placebo period, patients were randomly assigned to double-blind therapy with either placebo or 10, 40, or 80 mg fosinopril once daily for 4 weeks. If treatment goals were not met, chlorthalidone 25 mg/day was added for weeks 5 to 8. Thereafter, patients could enter the long-term, open-label phase and receive 10-80 mg/day fosinopril plus chlorthalidone, if needed. After 4 weeks of monotherapy, the average decreases in supine diastolic blood pressure were 9% (10 mg), 11.5% (40 mg), and 12.5% (80 mg) compared with 6% in the placebo group. After 8 weeks, the average decreases, with or without diuretic therapy, were 12.5-18.2%, compared with 10.8% with placebo. Blood pressure continued to be well controlled, and the patients showed no evidence of tachyphylaxis or tolerance through 12-15 months of treatment. Fosinopril was well tolerated. During the short-term phase, no patient withdrew because of adverse events possibly related to fosinopril; during the long-term phase, nine of 148 patients (6.1%) withdrew for that reason. In patients with mild-to-moderate hypertension, once-daily fosinopril (40 and 80 mg) provided significant antihypertensive effects with or without diuretic therapy. The 10 mg dose was effective in some patients and may be considered a starting dose.

Antihypertensive Agents↗
PubMed1988

Disposition of fosinopril sodium in healthy subjects.

1 Fosinopril sodium is the first phosphorus-containing angiotensin-converting enzyme (ACE) inhibitor to be studied clinically as an antihypertensive agent. It is an ester prodrug that is hydrolysed in vivo to the active diacid ACE inhibitor, SQ 27, 519. 2 In a three-way crossover study, nine healthy male subjects (age range 20-34 years) each received an intravenous 7.5 mg dose of SQ 27, 519-[14C] and two oral 10 mg doses of [14C]-fosinopril sodium, administered as a capsule and in solution. 3 After the intravenous dose of SQ 27, 519, the 0 to 96 h recovery of radioactivity averaged 44 and 46% of the dose in urine and faeces, respectively, indicating substantial biliary secretion. Only intact SQ 27, 519 was detected in the plasma, urine, and faeces following the intravenous dose of SQ 27, 519. 4 After oral doses of fosinopril sodium, about 75% of the radioactivity in plasma and urine was present as SQ 27, 519; the remainder corresponded mainly to a beta-glucuronide conjugate of SQ 27, 519 (15-20%), and a monohydroxylated analogue of SQ 27, 519 (about 5%). Negligible amounts of fosinopril sodium were present, indicating complete hydrolysis of the prodrug. 5 For the solution and capsule doses, respectively, the oral absorption of fosinopril sodium averaged 32% and 36% and the oral bioavailability of SQ 27, 519 averaged 25% and 29%. 6 The average values for clearance (39 ml min-1), renal clearance (17 ml min-1), Vss (10 1), and plasma protein binding (approximately 95%), indicated that SQ 27, 519 was slowly cleared from the body and not distributed extensively into extravascular sites.

Administration, Oral↗
PubMed1988

Pharmacokinetics of captopril in healthy subjects and in patients with cardiovascular diseases.

Captopril, the first orally active inhibitor of angiotensin-converting enzyme, is used widely in the treatment of hypertension and congestive heart failure. The pharmacokinetics of this agent have been studied extensively in healthy subjects and in patients with hypertension, congestive heart failure, and chronic renal failure. Captopril contains a sulphydryl group and binds readily to albumin and other plasma proteins. The drug also forms mixed disulphides with endogenous thiol-containing compounds (cysteine, glutathione), as well as the disulphide dimer of the parent compound. These components in blood and urine are measured collectively as total captopril. Because of the reversibility of the formation of these inactive disulphides, total captopril may serve as a reservoir of the pharmacologically active moiety, and thus contribute to a duration of action longer than that predicted by blood concentrations of unchanged captopril. To measure free or unchanged captopril concentrations, a chemical stabiliser must be added to the biological samples to prevent the formation of captopril disulphides ex vivo. In healthy subjects given captopril intravenously, the body clearance of captopril and steady-state volume of distribution were about 0.7 L/h/kg and 0.8 L/kg, respectively. The elimination half-life of unchanged captopril was approximately 2 hours. The primary route of elimination of captopril is the kidney. The renal clearance of unchanged captopril exceeds the glomerular filtration rate, due to active tubular secretion of the drug. In healthy subjects, about 70 to 75% of an oral dose is absorbed and the bioavailability of captopril is approximately 65%. Peak blood concentrations are reached about 45 to 60 minutes after oral administration. The bioavailability of captopril is not altered by age or concomitant medications including diuretics, procainamide, allopurinol, cimetidine or digoxin. However, the co-administration of food or antacids, or probenecid with captopril has been shown to diminish the bioavailability of the latter and decrease its clearance, respectively. The decreased bioavailability of captopril when taken with meals does not significantly alter clinical responses to the drug. Over a wide range of oral (10 to 150 mg) and intravenous doses (2.5 to 10 mg) captopril had linear kinetics in healthy volunteers. In healthy subjects with normal renal function and patients with congestive heart failure given captopril 3 times daily, blood concentrations of total captopril accumulated, whereas those of unchanged captopril did not. Severe renal insufficiency was associated with an accumulation of both unchanged and total captopril.(ABSTRACT TRUNCATED AT 400 WORDS)

Age Factors↗
PubMed1987

The antihypertensive effect of captopril in essential hypertension: relationship to prostaglandins and the kallikrein-kinin system.

Two groups, each with nine essential hypertensive patients, were maintained on 10 mmol sodium daily over 14-17 days and treated in this sequence: placebo; captopril (25 or 50 mg given thrice daily) or indomethacin (50 mg given thrice daily) alone; captopril plus indomethacin, and (4) captopril alone. The initial fall in mean blood pressure induced by captopril (118 +/- 1 to 102 +/- 1 mmHg) was unaffected by the addition of indomethacin. However, if indomethacin treatment preceded captopril, the antihypertensive effect was attenuated (116 +/- 4 to 109 +/- 4), and was associated with significant reductions in urinary prostaglandin and kinin excretion. Addition of captopril to indomethacin returned kinin excretion to placebo levels but did not affect indomethacin-induced reduction in prostaglandin excretion. Captopril alone stimulated plasma renin activity (PRA) fivefold; aldosterone excretion was lowered by 25% and further reduced by indomethacin. Thus, when captopril and indomethacin are administered together, the order of administration is critical to the antihypertensive effect of captopril.

Adult↗
PubMed1986

Effectiveness of low-dose nadolol for ventricular arrhythmias.

To determine the minimal effective dose of nadolol to suppress frequent ventricular premature complexes (VPCs), 23 patients with at least 30 VPCs/hour on 2 baseline 24-hour Holter recordings were studied. The initial dose of nadolol was 10 mg/day orally, and this dose was doubled at weekly intervals until arrhythmia suppression was achieved, adverse effects appeared, or a maximal dose of 160 mg/day was reached. After each dose level a 24-hour ambulatory Holter monitor was recorded. A pharmacokinetic trial was conducted in patients who responded to nadolol treatment. Frequent VPCs were suppressed at least 75% by nadolol in 11 of 23 patients (48%) and the minimal effective dose was 10 mg/day in 3 patients, 20 mg/day in 4, 40 mg/day in 3 and 80 mg/day in 1 patient. At these doses, minimal steady-state levels of nadolol in serum (Cmin) ranged from 3.9 to 47.0 ng/ml, and these serum concentrations were proportional to the oral dose of nadolol (r = 0.753, p less than 0.001). No relation, however, was observed between Cmin levels and percent reduction of VPCs. Cmin and heart rate changes were comparable between responders and nonresponders, suggesting that the degree of beta blockade was similar between these 2 groups. Adverse reactions were noted in 6 patients, and 2 had an asymptomatic increase in the frequency of VPCs and 1 patient an increase in beats of ventricular tachycardia. This study details the importance of selecting an individualized dose for nadolol for control of ventricular arrhythmias; in more than half of the patients doses of 20 mg/day or less were effective.

Adolescent↗
PubMed1984

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.

Adolescent↗
PubMed1984

Nadolol in hypertensive patients maintained on long-term hemodialysis.

The pharmacokinetics, efficacy, and safety of nadolol were evaluated in hypertensive patients maintained on long-term hemodialysis. In nine patients the plasma elimination half-life of unchanged nadolol averaged 26 hours following a single 40 mg oral dose during the interdialytic period. Nineteen patients received nadolol once after each dialysis session. In addition, 12 of the 19 patients also received hydralazine and/or furosemide daily. Predialysis blood pressures and heart rates were significantly lower with nadolol than with combination or single therapy with conventional antihypertensive drugs, including other beta blockers. Nadolol administered only after each dialysis session (i.e., two or three times a week), in conjunction with hydralazine and/or furosemide, is an effective antihypertensive agent in hypertensive patients receiving long-term hemodialysis.

Adrenergic beta-Antagonists↗
PubMed1984

Comparative effects of propranolol and nadolol on renal blood flow in normal rats and rats with congestive heart failure.

Mean arterial blood pressure (MAP), heart rate (HR), renal blood flow (RBF), and renal vascular resistance (RVR) were determined before and during an infusion of propranolol (18 mg/kg/hr) or nadolol (30 mg/kg/hr) in anesthetized Munich-Wistar rats with normal cardiac function. Eight rats treated with propranolol had significant reductions in MAP (110 to 98 mm Hg; p less than 0.05) and HR (316 to 242 bpm; p less than 0.01), accompanied by a 24% decrease in RBF (5.9 to 4.5 ml/min; p less than 0.05) and a 22% increase in RVR (19.4 to 23.7 mm Hg/ml/min; p less than 0.05). Although nadolol also reduced MAP (104 to 93 mm Hg; p less than 0.01) and HR (315 to 268 bpm; p less than 0.05) in eight other rats, RBF and RVR remained unchanged from baseline levels. Thus, despite similar decrements in MAP and HR, propranolol decreased renal perfusion, whereas nadolol maintained it in animals with noninfarcted myocardium. These parameters were also evaluated in rats with congestive heart failure induced by myocardial infarction at least 3 weeks prior to their receiving either propranolol (18 mg/kg/hr; n = 6) or nadolol (30 mg/kg/hr; n = 6). In the basal state, rats with congestive heart failure had significantly (p less than 0.05) lower MAP, HR, and RBF and higher (p less than 0.01) RVR compared with control rats. Propranolol and nadolol induced comparable falls (p less than 0.05) in MAP and HR. Whereas RBF tended to fall with propranolol (3.3 to 2.4 ml/min), renal perfusion was well maintained with nadolol (3.4 to 3.8 ml/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1984

Elimination kinetics of captopril in patients with renal failure.

Captopril kinetics were determined after a 100-mg oral dose of 14C-captopril in 21 patients with various degrees of renal impairment. Elimination kinetics of captopril were evaluated by model-independent methods. The body clearance (ClB) of captopril decreased steadily with decreasing creatinine clearance (ClCr) from 5.2 ml/min/kg for mild renal failure patients to 1.6 ml/min/kg for hemodialysis patients during an interdialytic period. In patients with mild renal impairment, renal and nonrenal clearances of captopril averaged 2.2 and 3.0 ml/min/kg, respectively, and fell (P less than 0.001) to 0.2 and 1.5 ml/min/kg in patients with severe renal impairment. There were no significant differences in the extent of total cumulative excretion (fecal plus urinary) of radioactivity over a 96- to 120-hr period between the patients with mild, moderate, and severe renal impairment. The 48-hr renal excretion of captopril averaged 29, 21, and 8% of the dose in the mild, moderate, and severe renally impaired groups. In five additional hemodialysis patients, the mean dialyzer clearance of captopril averaged 120 ml/min. Approximately 35% of the dose was recovered in the 4-hr dialysate. Based on the above findings, a reduction in the dose of captopril is necessary in patients with renal failure.

Adult↗
PubMed1983

Relative contribution of vasopressin and angiotensin II to the altered renal microcirculatory dynamics in two-kidney Goldblatt hypertension.

The renal microcirculation was assessed in non-clipped kidneys of 23 Munich-Wistar rats with two-kidney one-clip Goldblatt hypertension. Four weeks after placement of a renal arterial clip, mean systemic arterial pressure averaged 163 +/- 5 mm Hg in hypertensive rats as compared to 108 +/- 2 in sham-operated controls (n = 6 rats). Non-clipped kidneys in hypertensive rats were characterized by higher glomerular capillary hydraulic pressures, single nephron glomerular filtration rate, and afferent arteriolar resistance. The glomerular capillary ultrafiltration coefficient was significantly reduced in hypertensive rats. In 10 of these rats, intravenous infusion of the angiotensin antagonist, saralasin, or the converting enzyme inhibitor, SQ20881, led to significant reductions in systemic arterial pressure and in afferent and efferent arteriolar resistance, on average by 8 +/- 3%, 15 +/- 4%, 28 +/- 5%, respectively. These changes were associated with significant increase in glomerular plasma flow, while ultrafiltration coefficient remained unaffected. In the presence of saralasin or SQ20881, infusion of a specific antagonist of the vascular action of arginine vasopressin led to significant systemic but not renal vasodilation. Thus, whereas systemic arterial pressure fell further, on average by 23 +/- 2%, renal arteriolar resistance remained constant, resulting in marked reduction in glomerular capillary hydraulic pressures (by 18 +/- 2%) and glomerular plasma flow rate (by 28 +/- 10%). Because of these pronounced reductions in glomerular pressures and flows induced by vasopressin antagonist, single nephron glomerular filtration rate fell markedly in hypertensive rats (by 34 +/- 6%) despite normalization of ultrafiltration coefficient. When hypertensive rats (n = 7) were treated with vasopressin antagonist alone, a modest fall in systemic arterial pressure was again observed in the absence of changes in renal arteriolar resistance. Due to this selective extrarenal vasodilatory action of vasopressin antagonist, glomerular capillary hydraulic pressure, plasma flow rate, and single nephron glomerular filtration rate again fell markedly. When these vasopressin antagonist pre-treated hypertensive rats were given saralasin or SQ20881, marked reductions in renal arteriolar resistance were observed in association with a significant increase in glomerular plasma flow rate. These observations made during acute inhibition of angiotensin II and vasopressin indicate that both of these vasopressin hormones may play important roles in maintaining systemic hypertension in hypertensive rat. By virtue of its preferential constrictor effects on extrarenal rather than renal vasculature vasopressin serves to maintain high glomerular pressures and flows in the non-clipped kidney of Goldblatt hypertensive rats.

Angiotensin II↗
PubMed1982

Preserved renal perfusion during treatment of essential hypertension with the beta blocker nadolol.

Several beta-adrenergic antagonists impair renal perfusion during treatment of hypertension in man. The acute and chronic effects of a new noncardioselective beta blocker, nadolol, on renal hemodynamics, intravascular volume, and renal electrolyte excretion were studied in 10 men with essential hypertension. Oral nadolol normalized systemic blood pressure without impairment of glomerular filtration rate or renal blood flow, indicating preserved renal blood flow and glomerular filtration rate autoregulation. Intravascular volume and renal excretion of electrolytes were similarly unaltered. Once-daily nadolol lowers blood pressure without renal hemodynamic of functional embarrassment.

Adrenergic beta-Antagonists↗
PubMed1982

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 56%. 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).

Adult↗