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Biomedical subjects

A Karim

Publications and source records attributed to A Karim.

At least 163 records · Page 9Linked to original sources
PubMed1977

Ring D oxygenated Spirolactones. Characterization of human metabolic product of spironolactone.

15alpha-Hydroxycanrenone (1b) was prepared from canrenone (1a) by microbiological oxidation with a penicillium species. The product was identical with one obtained from the metabolism of spironolactone(3) in human. Oxidation of 1b with Jones regent furnished the corresponding 15-oxocanrenone (1d) which underwent base-catalyzed beta elimination to generate an alpha,beta-unsaturated cyclopentenone system. 15alpha-Hydroxycanrenone (1b) failed to show antimineralocorticoid activity at the screening dose of 2.4 mg while the oxo derivative 1d exhibited approximately 15% the activity of 3. Since the activity of canrenone is 38% that of spironolactone, introduction of the carbonyl group at the 15 position of canrenone resulted in a reduction in activity. This effect is opposite to that observed with 6-dehydroprogesterone.

Animals↗
PubMed1977

Disopyramide phosphate: tissue uptake and relationship between drug concentrations in the plasma and myocardium of rats.

Tissue uptake of total-14C and disopyramide (DP) was examined in rats following 5 to 100 mg/kg doses of [14C]-disopyramide phosphate [14C-DPP]. Disopyramide was the major 14C constituent in the plasma or tissues. The gastrointestinal absorption of [14C]-DPP was 86% as determined from the areas under the plasma total-14C concentration-time curves following 10 mg/kg oral or i.v. administration. Total-14C was widely distributed in tissues, and at 2 hr the highest uptake occurred in the fat, liver and spleen giving concentrations ranging from 7 to 15 times that in plasma. In the thymus, adrenals, lungs, salivary glands, testes and muscle the concentrations were about twice that in plasma, in the heart and eyes similar to that in plasma, and in the brain less than one-third that in plasma. The uptake and elimination characteristics of total-14C or DP in plasma and myocardium were similar. The two-hour plasma or myocardium DP concentrations were linearly related to the oral dose in the 5 to 50 mg/kg range. In three days about 30% (oral) and 39% (i.v.) of the 14C dose (10 mg/kg) was excreted in the urine, 64% (oral) and 54% (i.v.) in the feces, and less than 2.1% remained in the carcass. The composition of the urinary and fecal metabolites was similar after oral or i.v. administration of the drug.

Administration, Oral↗
PubMed1976

Spironolactone. I. Disposition and metabolism.

This study describes absorption, excretion, and metabolism of[20(-3)H]-spironolactone (SP) in 5 healthy men. After a single oral dose (200 mg + 200 muCi) of the drug given in alcoholic solution, the peak serum levels of the ethyl acetate-extractable tritium and the dethioacetylated metabolite canrenone were 763 +/- 400 ng/ml (mean +/- SD) and 415 +/- 145 ng/ml, respectively. These levels occurred within 3 hr. The serum half-life (T1/2) of the extractable materials was 37.3 +/- 6.53 hr. Canrenone levels declined in two phases. The T1/2 from 2.5 to 12 hr was 4.42 +/- 1.07 hr and from 12 to 72 hr was 16.8 +/- 2.75 hr. In the blood both SP and canrenone were confined largely in the plasma, and their protein binding exceeded 89% at concentrations of 550 and 710 ng/ml, respectively. In 5 days 31.6 +/- 5.87% of the radioactivity was excreted in the urine and 22.7 +/- 14.1% in the feces. Unchanged SP was not detected in the urine. The major urinary metabolites were canrenone (5.04 +/- 2.83% of dose), 6beta-OH-sulfoxide (5.21 +/- 0.93% of dose), and canrenoate ester glucuronide (6.2% of dose).

Adult↗
PubMed1976

Spironolactone. II. Bioavailability.

The bioavailability of commercial 25-mg spironolactone tablets and a new tablet preparation containing 100 mg of the drug has been determined in 12 healthy male subjects. After a 200-mg oral dose of the drug given in a solution of polyethylene glycol-400, the peak plasma level of the dethioacetylated metabolite canrenone was 633 +/- 154 ng/ml (mean +/- SD) and was reached at 1.4 +/- 0.43 hr. This peak was higher and was achieved earlier than after either eight 25-mg tablets (480 +/- 155 ng/ml at 2.9 +/- 1.03 hr) or two 100-mg tablets (474 +/- 182 ng/ml at 3.0 +/- 1.37 hr). From the ratio of the 24-hr area under the plasma concentration-time curves, the bioavailabilities of the two tablet preparations relative to the solution were 99.6 +/- 18.2% and 92.1 +/- 22.9%, respectively. The amount of canrenone excreted in the urine by 48 hr was 4.48 +/- 1.26 mg (solution), 6.36 +/- 2.02 mg (eight 25-mg tablets), and 7.81 +/- 1.87 mg (two 100-mg tablets), representing 2% to 4% of the administered dose. It is concluded that urinary excretion of canrenone alone is not a reliable method for determining the bioavailability of spironolactone.

Administration, Oral↗
PubMed1976

Spironolactone. III. Canrenone--maximum and minimum steady-state plasma levels.

Steady-state plasma levels of canrenone have been examined in 23 healthy men who received repeated doses of spironolactone for 15 days. The dose regimens were 200 mg once a day and 50 mg 4 times a day. With both treatments the steady-state levels were reached after 3 to 4 days. With once-a-day treatment, the maximum and minimum steady-state levels were about 500 and 100 ng/ml, respectively. The minimum levels with treatment 4 times a day were about 200 ng/ml. The post steady-state half-life of canrenone with once-a-day treatment (19.2 +/- 6.57 hr) was longer (p less than 0.01) than the half-life obtained in the 4 times-a-day treatment (12.5 +/- 3.39 hr). The former half-life was similar to the log-linear phase half-life of canrenone in the single-dose studies.

Adult↗
PubMed1976

In vitro and in vivo availability of spironolactone from oral dosage forms.

Tablet formulations of spironolactone with hydrochlorothiazide were studied in vitro and in vivo to evaluate the effect of formulation parameters on the bioavailability of spironolactone. The time required for 50% tablet dissolution (T50) in simulated gastric fluid was linearly correlated with the disintegration times of four experimental formulations and one commercial tablet of spironolactone and hydrochlorothiazide. Bioavailability studies were conducted in four healthy, female beagle dogs. The mean time to peak concentration of canrenone,f cancrenone, the major metabolite of spironolactone, was proportional to the T50 dissolution parameter. A study of spironolactone administered orally with and without hydrochlorothiazide showed that the bioavailability of spironolactone is not affected by hydrochlorothiazide. No significant difference in the bioavailability of spironolactone from one 100-mg and four 25-mg tablets were observed. Estimates of some pharmacokinetic parameters for canrenone closely agreed with those previously reported.

Animals↗
PubMed1973

Preparation of metabolites of spironolactone by microbial oxygenation.

It has been postulated that 3-(3-oxo-7alpha-methylthio-4-androsten-17alpha-yl)propionic acid gamma-lactone (I) is a key intermediate in the metabolism of the anti-aldosterone agent, spironolactone (3-[3-oxo-7alpha-acetylthio-17beta-hydroxy-4-androsten-17alpha-yl] propionic acid gamma-lactone). In the present study it was found that microbial oxygenation of I by Chaetomium cochloides QM 624 gave three metabolites which retained sulfur in their molecules and were found to be identical to the human metabolites of spironolactone.

Ascomycota↗