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)

By inhibiting ACE, captopril blocks the conversion of AI or AII and augments the effects of bradykinin both in vitro and in vivo. In rats, dogs, and monkeys with 2-kidney renal hypertension, orally administered captopril rapidly and markedly reduces blood pressure; this antihypertensive effect apparently occurs via a renin-dependent mechanism; that is, the inhibition of ACE. In 1-kidney renal hypertension studies in rats and dogs, it was determined that oral doses of captopril markedly lowered blood pressure, but only after several days of dosing; the mechanism is thought to be non-renin dependent. In SHR, daily oral doses of captopril progressively lowered blood pressure; normal levels were attained by the sixth month. In all species studied, the reduction in blood pressure resulted from a reduction in total peripheral resistance; cardiac output remained unchanged or increased. In humans, captopril reduces blood pressure in patients with essential hypertension with low, normal, and high renin levels, and in patients with renovascular hypertension and hypertension associated with chronic renal failure. In hypertensive patients with high plasma renin activity, captopril apparently exerts most of its pharmacologic effects through inhibition of ACE. The means by which captopril reduces high blood pressure associated with low or normal PRA is not known, but it is clear that captopril does not act on an overactive plasma renin-angiotensin system in these cases. The antihypertensive effect of captopril is enhanced when it is given in combination with a diuretic or after salt depletion. Captopril was rapidly and well absorbed in all species tested, including man. Studies in rodents indicated that ingestion of food caused a reduction in the extent of absorption and bioavailability of captopril. Captopril and/or its metabolites were distributed extensively and rapidly throughout most tissues of normal rats; no radioactivity was detected in the brain. In vitro and in vivo, captopril formed disulfide bonds with albumin and other proteins. This binding was reversible in nature. In vitro studies in blood indicates that the disulfide dimer of captopril and mixed disulfides of captopril with L-cysteine and glutathione were formed. In intact blood cells, captopril remained in the reduced form (sulfhydryl), whereas in whole blood or plasma, captopril was converted to its disulfide dimer and other oxidative products. Biotransformation of captopril may involve both enzymatic and nonenzymatic processes.(ABSTRACT TRUNCATED AT 400 WORDS)

The disposition of [3H]zeranol has been studied in the female Wistar rat, New Zealand rabbit, beagle dog, rhesus monkey and man. The blood elimination half-life of total radioactivity in rabbit was 26 h, monkey 18 h and man 22 h. In all species studied the drug was absorbed, oxidized and/or conjugated, and was extensively excreted via the bile in all species except rabbit and man, in which urinary excretion predominated. Blood total radioactivity in man probably consisted entirely of conjugates of zeranol and/or its metabolites. Urinary metabolites in all species included conjugates (beta-glucuronides and/or sulphates) of zeranol and the major metabolite zearalanone. A more polar minor metabolite was isolated from human urine and was shown to be hydroxy-zeranol. Taleranol (7 beta-zearalanol, the lower-melting diastereoisomer), a probable metabolite of zeranol (7 alpha-zearalanol, the higher-melting diastereoisomer) in animals and in man, was shown to be a urinary metabolite in a female New Zealand white rabbit which had received [3H]zeranol (8 mg/kg per day) for seven days. A reverse isotope dilution method was developed for the quantification of both diastereoisomers of zearalanol, and also zearalanone, in urine.

Captopril, an angiotensin-converting enzyme inhibitor with antihypertensive properties, was given by mouth and intravenously in 10-mg doses to five healthy subjects. After intravenous dosing, semilogarithmic plots of captopril blood levels : time showed a triexponential decay. Data were analyzed using an open three-compartment model. The average volume of distribution (Vd) was 0.2 l/kg for the central compartment and 2 l/kg for the elimination (beta) phase. The Vd at steady-state was 0.7 l/kg. The total body clearance of captopril averaged 0.8 l/kg/hr and the mean blood half-life during the beta phase was 1.9 hr. In the 0- to 96-hr urine, after intravenous and oral drug, excretion of radioactivity accounted for 87% and 61% of dose. In the 0- to 24-hr urine, averages of 38% (intravenous) and 24% (oral) of the doses were excreted as unchanged captopril. Absolute absorption of the radioactive oral dose was 71% and the absolute oral bioavailability of captopril was 62%.