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Clinical Pharmacology and Therapeutics Jan 1994The in vivo stability of tolmetin-plasma protein adducts was characterized in six healthy human volunteers after a 400 mg single dose and after a multiple-dose regimen...
The in vivo stability of tolmetin-plasma protein adducts was characterized in six healthy human volunteers after a 400 mg single dose and after a multiple-dose regimen of 400 mg tolmetin every 12 hours for 10 days. Although the mean +/- SD maximum bound concentration was only 2.72 +/- 0.98 ng drug/mg protein after a single dose, it was almost an order of magnitude higher after multiple dosing. The protein adduct exhibited an average half-life of 4.8 +/- 0.9 days in contrast to the much shorter 5-hour half-lives for tolmetin and its glucuronide.
Topics: Adult; Blood Proteins; Drug Administration Schedule; Female; Humans; Male; Protein Binding; Tolmetin
PubMed: 8299313
DOI: 10.1038/clpt.1994.5 -
Archives of Internal Medicine May 1982
Topics: Analgesics; Bone Diseases; Hemophilia A; Humans; Ibuprofen; Joint Diseases; Tolmetin
PubMed: 7082108
DOI: No ID Found -
Drug Metabolism and Disposition: the... 1976Tolmetin, 1-methyl-(5-p-toluoyl)pyrrole-2-acetic acid, is a new, nonsteroidal, anti-inflammatory agent. After oral administration of tolmetin-14C to rats and mice,... (Comparative Study)
Comparative Study
Tolmetin, 1-methyl-(5-p-toluoyl)pyrrole-2-acetic acid, is a new, nonsteroidal, anti-inflammatory agent. After oral administration of tolmetin-14C to rats and mice, sequential microsamples of blood were obtained from the ophthalmic venous plexus via the orbital sinus. Plasma was collected after centrifugation, and microaliquots of each plasma sample were analyzed. The total radioactivity and thin-layer chromatographic assays used permitted quantitation of tolmetin, its dicarboxylic acid metabolite, and (by difference) all other metabolites collectively for each sample. Time-course data on plasma levels were obtained for individual rats and mice. The plasma elimination half-life of tolmetin was estimated at 0.67 +/- 0.13 hr (mean +/- SD) in male rats, 1.4 +/- 0.6 hr in female rats, 1.2 +/- 0.3 hr in male mice, and 1.0 +/- 0.0 hr in female mice. A one-compartment open model was used.
Topics: Administration, Oral; Animals; Chromatography, Thin Layer; Female; Half-Life; Kinetics; Male; Methods; Mice; Models, Biological; Pyrroles; Rats; Tolmetin
PubMed: 10146
DOI: No ID Found -
Journal of Clinical Pharmacology Jul 1983Data from over 1000 patients with rheumatoid arthritis who received tolmetin sodium in double-blind and open studies have been pooled to assess long-term efficacy and...
Data from over 1000 patients with rheumatoid arthritis who received tolmetin sodium in double-blind and open studies have been pooled to assess long-term efficacy and safety. Duration of the studies was 12 weeks to 48 months. Mean age of patients was 54 years; ratio of males to females was 1:3. The results showed that tolmetin provided rapid onset of action and continuous progressive decrease in symptoms in all measurements of inflammation. Mean number of painful joints was reduced from 22 at baseline to 16 at one month, to 9 at one year, and to 6 at two years. Duration of morning stiffness was 155 minutes at baseline, 123 minutes at one month, 74 minutes at one year, and 78 minutes at two years. The final global evaluation by the investigators showed that 61 per cent of patients had a marked or moderate response. Mean erythrocyte sedimentation rates did not increase during therapy with tolmetin. Initial dose of tolmetin in the patients pooled for this analysis was generally 600 to 800 mg/day, and the mean dose throughout the study was 1256 mg/day. The drug was well tolerated overall. As anticipated, gastrointestinal symptoms were the most frequently reported; nausea was experienced by 13 per cent of the patients at some time during therapy, and gastrointestinal distress, dyspepsia, or abdominal pain was reported by approximately 8.6 per cent each. Only 12.7 per cent of patients discontinued tolmetin because of untoward reactions; 15.9 per cent of patients discontinued because of insufficient therapeutic response. The results of these long-term studies of patients with rheumatoid arthritis demonstrated that tolmetin is an effective antiinflammatory agent with an acceptable record of safety.
Topics: Adolescent; Adult; Aged; Arthritis, Rheumatoid; Double-Blind Method; Female; Humans; Male; Middle Aged; Pyrroles; Time Factors; Tolmetin
PubMed: 6886030
DOI: 10.1002/j.1552-4604.1983.tb02739.x -
Arzneimittel-Forschung 1983Concentrations of the antiinflammatory agent tolmetin have been measured by HPLC in inflamed and non-inflamed rat tissues after oral administration of tolmetin sodium...
Concentrations of the antiinflammatory agent tolmetin have been measured by HPLC in inflamed and non-inflamed rat tissues after oral administration of tolmetin sodium dihydrate in solution (100 mg free acid/kg) and after topical administration of tolmetin (Tolectin gel, 1 g of a 5% gel, 250 mg free acid/kg). After oral administration of tolmetin, there was marked localisation of the drug in inflamed rat paws. Concentrations of tolmetin were significantly greater in inflamed paws than those in non-inflamed paws at each time studied (e.g. at 3 h after dosing, inflamed paw 30.5 micrograms/g, non-inflamed paw 14.9 micrograms/g). After a single topical application of tolmetin gel to the shaved backs of rats, tolmetin was well absorbed percutaneously into the non-inflamed dorsal muscle. After repeated topical application of tolmetin gel to the shaved backs of rats, daily for 4 consecutive days, concentrations of tolmetin (total micrograms/paw) similar in inflamed paws and in non-inflamed paws. After topical administration of tolmetin gel to rat paws, tolmetin was transported from treated paws to untreated paws, e.g. from non-inflamed paws to inflamed paws and vice versa. These studies showed that tolmetin applied topically reaches inflamed tissues in concentrations that exceed those in plasma.
Topics: Administration, Topical; Animals; Inflammation; Male; Muscles; Pyrroles; Rats; Rats, Inbred Strains; Tolmetin
PubMed: 6686452
DOI: No ID Found -
Journal of Pharmaceutical and... Nov 2013The interaction of tolmetin (TOL) with human serum albumin (HSA) in physiological buffer solution (pH 7.4) was studied by fluorescence and UV-vis absorption spectroscopy...
The interaction of tolmetin (TOL) with human serum albumin (HSA) in physiological buffer solution (pH 7.4) was studied by fluorescence and UV-vis absorption spectroscopy at different temperatures, combined with time-resolved fluorescence measurements. The experimental results showed that there was a strong fluorescence quenching of HSA by tolmetin. Using the continuous variation method, a single class of binding sites for TOL on HSA was put in evidence. The binding constants Ka were calculated at different temperatures, using a nonlinear fit to the experimental data, and the thermodynamic parameters ΔH(0), ΔS(0) and ΔG(0) were given. The obtained thermodynamic signature suggests that at least van der Waals and electrostatic type interactions are present. Quenching efficiency calculations, based on steady state and time-resolved spectroscopy, indicate that both static and dynamic quenching mechanisms are present.
Topics: Binding Sites; Humans; Serum Albumin; Thermodynamics; Tolmetin
PubMed: 23973633
DOI: 10.1016/j.jpba.2013.07.032 -
European Journal of Clinical... Dec 1977
Topics: Adult; Antacids; Drug Interactions; Humans; Kinetics; Male; Pyrroles; Time Factors; Tolmetin
PubMed: 598416
DOI: 10.1007/BF00561061 -
Drug Metabolism and Disposition: the... Mar 1995The structures of adducts formed from in vitro incubation of a drug (tolmetin) glucuronide (TG) and human serum albumin (HSA), and the preferred binding sites on this...
The structures of adducts formed from in vitro incubation of a drug (tolmetin) glucuronide (TG) and human serum albumin (HSA), and the preferred binding sites on this protein were determined by mass spectrometry. In addition, the concentration dependence of covalent modification of HSA by TG was studied at three different concentration ratios of TG to HSA. Protein adducts were enzymatically digested and peptide fragments were separated by HPLC. Tolmetin-containing peptides (indicated by absorbance at 313 nm) were analyzed by liquid secondary-ion mass spectrometry, continuous flow-fast atom bombardment mass spectrometry, and collision-induced dissociation using a four-sector tandem mass spectrometer, matrix-assisted laser desorption ionization-time-of-flight-mass spectrometry, and in selected cases by Edman sequencing. The identified peptides contained tolmetin linked covalently via a glucuronic acid to a protein lysine group (lysine 199 and to a lesser extent lysines 195 and 525) or tolmetin directly linked to lysines (lysines 199 and 541), serines (serines 220, 232, and 480), or arginines (arginine 222). In addition, there was indirect evidence for binding of TG to lysine 541, and binding of tolmetin to arginine 521. Our results establish that the binding of these reactive metabolites to nucleophilic sites of proteins occur via two different mechanisms: one involving imine (Schiff base) formation and the other involving nucleophilic displacement of glucuronic acid. Our data suggest, however, that the former, in which the glucuronic acid moiety of the acyl glucuronide is retained within the adducts, is favored at lower (closer to physiological) metabolite concentrations.
Topics: Amino Acid Sequence; Binding Sites; Chemical Fractionation; Humans; Mass Spectrometry; Molecular Sequence Data; Peptides; Protein Binding; Serum Albumin; Tolmetin
PubMed: 7628303
DOI: No ID Found -
Clinical Pharmacology and Therapeutics Sep 1982Tolmetin kinetics were determined in the plasma and synovial fluid of five rheumatoid arthritis patients after they had ingested tolmetin (400 mg every 6 hr) for 7 days....
Tolmetin kinetics were determined in the plasma and synovial fluid of five rheumatoid arthritis patients after they had ingested tolmetin (400 mg every 6 hr) for 7 days. Tolmetin was rapidly absorbed, with average peak levels in plasma and synovial fluid occurring at 45 min and 2 hr. The drug concentration in synovial fluid was higher than that in plasma for prolonged periods, while the rates of elimination from both plasma and synovial fluid were similar. The average half-lives of tolmetin in plasma and synovial fluid were 6.77 +/- 1.47 hr and 6.90 +/- 2.3 hr. Total prostaglandin E levels in synovial fluid of these patients were suppressed for at least 24 hr after the last dose of tolmetin, suggesting that PGE synthesis continues to be suppressed even by the very low concentrations of tolmetin remaining after 24 hr.
Topics: Adult; Arthritis, Rheumatoid; Female; Half-Life; Humans; Kinetics; Male; Middle Aged; Prostaglandins E; Pyrroles; Synovial Fluid; Tolmetin
PubMed: 7105628
DOI: 10.1038/clpt.1982.174 -
Anaesthesia and Intensive Care Aug 1993
Topics: Analgesics; Anaphylaxis; Female; Herniorrhaphy; Humans; Ketorolac; Middle Aged; Pain, Postoperative; Tolmetin
PubMed: 8214561
DOI: No ID Found