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The absorption and metabolism of the disulfide dimer conjugate of captopril has been studied in the rat following both oral and intravenous dosing and compared with that of the active monomer, captopril. Metabolism of the dimer to captopril has been shown after both oral and intravenous administration of the dimer (10 mg/kg) with peak plasma levels of captopril (154 ng/ml) occurring at 1 hr post dose. By contrast the peak plasma level of captopril after oral administration of captopril (10 mg/kg) at the same dose was much higher at 678 ng/ml and also occurred at 1 hr post dose. Plasma captopril disulfide species were much higher than the plasma levels of captopril after the administration of either dimer or captopril and tended to persist for much longer than for monomeric captopril particularly after administration of the dimer. Both the dimer and its pharmacologically active product captopril were found in relatively large amounts in lung, kidney and liver following the oral administration of the dimer.

The urinary excretion of captopril has been studied in a bladder-cannulated rat model and compared with that obtained after co-administration with probenecid. Probenecid reduced significantly the urinary excretion of captopril from 41% to 21% of the administered dose over a 3-hr period and significantly lowered urine flow rates. In addition, the effect of probenecid on plasma levels of captopril and total captopril (captopril plus disulfides) after oral administration of the disulfide prodrug captopril dimer (10 mg/kg) has been studied in a conscious rat preparation. Co-administration of probenecid (20 mg/kg) given either orally or intravenously increased both the plasma levels of captopril and total captopril (captopril plus captopril disulfides) over a 4-hr period. A prolonged significant inhibition of plasma ACE after co-administration of probenecid and captopril dimer suggests that probenecid may be useful to prolong the action of captopril or the prodrug captopril dimer.

The presence of a methyltransferase enzyme in human red blood cells (RBCs) capable of S-methylation of captopril is described. The apparent Michaelis-Menten (Km) constant for captopril was 0.5 mM and the maximum velocity (Vmax) was 0.391 pmoles S-methylcaptopril (mg protein)-1 min-1. There is some evidence presented to show that S-methylcaptopril inhibited its own formation with a ki value of 5.81 mM. Captopril thiol methyltransferase activity was also examined in rat tissues and was found to be present in all tissue studied. Subcellular localisation studies in rat liver suggest that the enzyme was microsomal in origin. The order of activity was liver greater than heart greater than spleen greater than lung greater than kidney much greater than RBC (rat). This tissue distribution was quite different from previous studies using other thiol substrates and is consistent with more than one form of thiol methyltransferase enzyme in tissues.

A sensitive assay is described for quantitating plasma captopril levels. Captopril is an orally active inhibitor of angiotensin-converting enzyme. Blood from patients taking this drug was collected into tubes containing edetate and ascorbic acid, and the plasma was separated by centrifugation. After addition of an internal standard, the plasma was deproteinized and the supernate was adjusted to pH 6.5 N-(1-Pyrene)-maleimide was added to derivatize captopril and an internal standard to fluorescent adducts. These derivatives then were extracted into ethyl acetate-benzene (1:1) and separated from other derivatized thiols by high-performance liquid chromatography. The sensitivity of the assay was 150 pmoles/ml. Preliminary pharmacokinetics were obtained in patients taking captopril chronically for essential hypertension. After administration of 100 mg of captopril for patients who had fasted overnight, the plasma levels rose rapidly; peak levels were obtained at approximately 37 min. Thereafter, the plasma levels declined rapidly, and the terminal half-life was approximately 40 min. In these patients, the time course of the plasma levels did not reflect changes in blood pressure, so there appeared to be no direct relationship between plasma levels of the parent compound and blood pressure changes.

The tissue distribution of captopril, an antihypertensive drug possessing a free sulfhydryl group, and its sulfur-conjugated metabolites was studied in rats by gas chromatography-mass spectrometry at 15, 30 and 60 min following a single 10 mg/kg oral dose of captopril. It was found that tissue accumulation of captopril was rapid with both free and oxidized-forms already present at 15 min post-dose. A maximum concentration of captopril was achieved at 30 min in tissues studied, being substantially higher in kidney (14.2 micrograms/g), with lesser amounts occurring in liver, lung, heart, blood cells, spleen and plasma in that order. Oxidized disulfide forms of captopril were usually present in the same or slightly higher proportion than free captopril except for liver which only contained detectable disulfides at 15 min after oral dosing. S-methylcaptopril was also present at 30 min in all tissues examined with highest levels occurring in liver and kidney (1.05 micrograms/g) followed by plasma, lung, heart, spleen and blood cells.

The pharmacokinetic properties of captopril were studied in two groups of hypertensive patients; (1) those who had never taken captopril (acute group), and (2) those who had been taking captopril for at least 6 months (chronic group). It was found that after 100 mg of captopril orally, the mean peak plasma level in the chronic group was three times higher than that in the acute group while the area under the curve was twice as high in the chronic group. These data suggest that bioavailability increases with chronic administration, and thus it may be possible to reduce the dosage of captopril and still maintain blood pressure control while reducing side effects.

A gas chromatographic-mass spectrometric method is described for the simultaneous measurement of the novel anti-hypertensive drug captopril, and the following metabolites: captopril disulfide dimer, S-methyl captopril, and S-methyl captopril sulfone. With this method all derivatives can be chromatographed using conventional gas chromatography of hexafluoroisopropyl esters in one temperature-programmed run and these can then be quantitated using selected-ion monitoring techniques. Using urine or plasma, captopril, S-methyl captopril and the disulfide dimer of captopril in concentrations as low as 1 ng/ml, 10 ng/ml and 25 ng/ml, respectively can be detected. The reproducibility of the method is satisfactory both within-assay and inter-assay. This technique has demonstrated that the pattern of urinary excretion of these compounds in both man and rat was similar. Excretion of unchanged captopril, S-methyl captopril and the disulfide dimer over 6 h in man given captopril (50 or 100 mg) chronically was 18.3%, 0.97% and 3.06%, respectively. Corresponding excretion of these three compounds in the rat following a single 10 mg/kg dose was 18.3%, 2.69% and 1.8%, respectively. A possible sulfone oxidation product of S-methyl captopril was not detected in the urine of either man or rat.

The gastric and intestinal absorption of captopril, an orally active angiotensin-converting enzyme inhibitor was determined using rat in situ gastric pouch and intestinal loop techniques and compared with the absorption of another acidic drug, salicylic acid, whose absorption has been well established from both gastric and intestinal sites. Captopril absorption was determined at two initial intraluminal concentrations in acute (untreated) rats and in rats that had been chronically treated with captopril. Salicylic acid absorption was determined at one concentration in acute rats. During the 40-min experimental period, captopril absorption at the 4.6 mM dose from the gastric pouch was 17.0 +/- 1.8% and 17.9 +/- 5.4% in acute and chronically treated rats, respectively, and 33.6 +/- 9.2% and 23.7 +/- 7.6%, respectively, from the intestinal loop. At the 11.5 mM dose the captopril absorption in 40 min was 13.7 +/- 2.7% and 17.3 +/- 4.2% from the gastric pouch of acutely and chronically treated rats, respectively, and 17.8 +/- 4.2% and 22.9 +/- 3.3%, respectively, from the intestinal loop. As similar fractions of the different administered doses were absorbed from the respective gastric and intestinal sites in both acutely and chronically treated rats, the absorption process of captopril appears to be principally by passive diffusion and unaffected by chronic administration of captopril. In comparison, salicylic acid was absorbed more rapidly and to a greater extent from both the gastric and intestinal preparations. The percent of salicylic acid absorbed into the plasma at the 11.5 mM dose was 44.8 +/- 4.4% and 65.3 +/- 5.3% from the gastric and intestinal preparations, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

We have measured the plasma concentrations of captopril and total disulfide conjugates of captopril after a 50 mg oral dose in 6 uraemic patients on maintenance dialysis and in 8 hypertensive subjects with normal renal function. The mean peak plasma concentration of captopril was 2.5 times higher (0.447 micrograms X ml-1 vs 0.181 micrograms X ml-1) and the concentrations of the disulfides 4 times higher (3.62 micrograms X ml-1 vs 0.924 micrograms X ml-1) in the uraemic patients. Moreover captopril disulfide conjugates in the uraemic subjects reached peak concentrations at 8 h after the dose and subsequently felt. The apparent plasma half-time was 46 +/- 19 h. Only 15% of these conjugates were removed by dialysis. This marked accumulation of captopril conjugates was associated with a sustained fall in both systolic and diastolic blood pressures. In uraemic patients the mean maximum reduction in systolic and diastolic blood pressures were 37 +/- 7 mmHg and 24 +/- 9 mmHg respectively, occurring 6 h after the dose, compared with 8 +/- 7 and 8 +/- 1 mmHg respectively at 30 min in normal renal function patients. These results are consistent with the results of animal experiments, which show that captopril disulfides can be converted back to free captopril and can contribute to the antihypertensive effect of the drug. They provide a reationale for reducing the dose and frequency of administration of captopril in patients with significant renal impairment.

1. The formation of the S-methyl metabolite of captopril has been demonstrated for the first time in the urine of five patients receiving chronic captopril therapy. 2. Patients were studied following a 100 mg oral dose of captopril. 3. Excretion values for S-methylcaptopril were 0.66 mg and 0.31 mg at 0-3 h and 3-6 h postdose. Captopril excretion was at these two collections 15.5 mg and 2.3 mg, respectively.

Focuses on the occurrence of taste disturbance in patients treated with captopril. Function of captopril; Factors causing the development of adverse effects of captopril; Effect of captopril binds to zinc ion on the tissue zinc level.