ABSTRACT
A series of experiments has been performed in healthy male volunteers to investigate the disposition of orally administered disodium azodisalicylate, a potentially useful drug for the treatment of ulcerative colitis. The drug was given by mouth in doses of up to 2 g a day for six weeks and there were no adverse effects. Serum concentrations of the intact compound were low and the serum half-time was 4-12.8 days, probably because of a combination of a low clearance rate and a high apparent volume of distribution. Less than 5% of the ingested dose was excreted unchanged in the urine. Circulating concentrations of 5-ASA and N-acetyl-5-ASA were low and 30% of the equivalent daily dose was excreted in the urine, predominantly as N-acetyl-5-ASA. In most subjects more than 30% of the equivalent daily dose of 5-ASA was recovered from the faeces, either as 5-ASA itself or as the acetylated derivative. As 5-ASA has been shown to be the active therapeutic moiety of sulphasalazine, disodium azodisalicylate appears to be suitable for therapeutic trial in ulcerative colitis.
Subject(s)
Aminosalicylic Acids/metabolism , Adult , Aged , Aminosalicylic Acids/administration & dosage , Aminosalicylic Acids/adverse effects , Colitis, Ulcerative/drug therapy , Drug Administration Schedule , Feces/analysis , Half-Life , Humans , Kidney/metabolism , Kinetics , Male , Middle AgedABSTRACT
d-Propoxyphene kinetics was studied in 8 healthy male subjects after single oral doses of d-propoxyphene at 65, 130, and 190 mg and after slow intravenous infusion of 65 mg. Total urinary excretion (7 days) indicated complete oral absorption but systemic availability was reduced corresponding to fist-pass elimination of 30% to 70%. There was linearity between oral dose and the corresponding area under the plasma concentration/time curve of d-propoxyphene and the metabolite norpropoxyphene. The kinetic measurements showed 2- to 3-fold interindividual variations: oral clearance, 1.3 to 3.6 1/min; systemic clearance, 0.6 to 1.2 1/min; apparent volume of distribution, 700 to 1,800 1; d-propoxyphene half-life (t1/2), 8 to 24 hr; and norpropoxyphene t1/2, 18 to 29 hr. There were pronounced intraindividual dose-dependent variations in oral clearance in some subjects. The intravenous concentration curves indicated a 3-compartment distribution model.
Subject(s)
Dextropropoxyphene/administration & dosage , Administration, Oral , Adult , Dextropropoxyphene/blood , Dextropropoxyphene/urine , Drug Evaluation , Humans , Injections, Intravenous , Kinetics , MaleABSTRACT
The single-dose kinetics of D-propoxyphene, acetyl salicylic acid and phenazone, given in a combination tablet (Doleron), were compared in young and elderly subjects. Serial blood samples were taken 0--48 hours after administration. The plasma concentrations of propoxyphene and of its major metabolite, norporpoxyphene, were assessed by mass fragmentography, those of phenazone by gas chromatography, and those of acetyl salicylic acid plus salicylic acid by spectrofluorometry. Neither for propoxyphene, norpropoxyphene, acetyl salicylic acid nor phenazone did the areas under the concentration curves or the elimination half-lives differ between young and elderly subjects. These data do not provide pharmacokinetic support for a general reduction of the Doleron dosage in elderly subjects.
Subject(s)
Antipyrine/metabolism , Aspirin/metabolism , Dextropropoxyphene/metabolism , Administration, Oral , Adult , Age Factors , Aged , Antipyrine/administration & dosage , Aspirin/administration & dosage , Dextropropoxyphene/administration & dosage , Drug Combinations , Female , Humans , Intestinal Absorption , Male , TabletsABSTRACT
The influence of food intake on the bioavailability of three analgesic compounds--propoxyphene chloride, acetyl salicylic acid and phenazone--in a combination tablet, Doleron, has been examined in eight healthy volunteers. A single oral dose was given both on an empty stomach and together with a standardized breakfast meal. The plasma concentrations of propoxyphene, its major metabolite norpropoxyphene, salicylic acid and phenazone were determined by mass fragmentography, spectrofluorimetry and gas chromatography. Concomitant food intake had no consistent influence on the bioavailability of any of the components. Hence, doleron may be taken together with meals as well as between meals. Large interindividual variations in propoxyphene and phenazone concentrations were found, indicating that an optimal effect will not always be obtained by standard doses.
Subject(s)
Antipyrine/metabolism , Aspirin/metabolism , Dextropropoxyphene/metabolism , Food , Adult , Biological Availability , Drug Combinations , Fasting , Female , Humans , MaleABSTRACT
Bacampicillin (proposed international nonproprietary name), 1'-ethoxycarbonyloxyethyl 6-(d-alpha-aminophenylacetamido)penicillanate, is a new orally well-absorbed penicillin, highly active in vivo due to rapid transformation into ampicillin. The compound is stable in vitro at gastric pH and hydrolyzed slowly to ampicillin at neutral pH but very rapidly in the presence of biological fluids, e.g., tissue homogenates or serum. In vivo the transformation into ampicillin is so rapid that no unchanged compound could be detected in the blood after oral administration of bacampicillin to rats, dogs, and humans. On oral administration to mice, rats, and dogs, bacampicillin was found to be better absorbed than ampicillin, giving higher and earlier peak blood levels of ampicillin. The bioavailability of bacampicillin in rats and dogs was three to four times higher than that of an equimolar amount of ampicillin. On oral administration to rats, bacampicillin was found to give higher levels of ampicillin in organs such as the kidney, liver, and spleen than ampicillin itself. In "tissue cages" in rats, higher transudate levels of antibiotic were found after oral administration of bacampicillin than after ampicillin. On oral treatment of experimentally infected mice, bacampicillin was found to be more active than ampicillin.
Subject(s)
Ampicillin/analogs & derivatives , Ampicillin/metabolism , Ampicillin/therapeutic use , Animals , Bacterial Infections/drug therapy , Dogs , Female , Hydrolysis , Intestinal Absorption , Male , Mice , Rats , Species SpecificityABSTRACT
1. The absorption from the respiratory tract and biotransformation of three bronchodilating drugs, terbutaline, ibuterol (diisobutyrate ester of terbutaline) and isoproterenol, have been studied in rats after endotracheal instillation. 2. At 2-15 min after dosage, ibuterol is more rapidly absorbed from the respiratory tract than terbutaline, but later (15-35 min), absorption of ibuterol is about the same as terbutaline. Absorption of isoproterenol is rapid throughout the experiment. Absorption rates have been related to the physical-chemical properties of the compounds. 3. No significant biotransformation of terbutaline was noted in the rat lung at any time after dosage, but ibuterol is extensively hydrolysed to terbutaline. Extensive biotransformation of isoproterenol to 3-methoxy-isoproterenol and an unidentified metabolite occurred. Metabolites of terbutaline and isoproterenol were found in serum and liver.
