RESUMO
This paper describes a quantitative assay of 2-(2-thiophenecarboxy)benzoic acid and its systemic metabolites, namely salicylic acid and thiophenecarboxylic acid, by high-performance liquid chromatography with ultraviolet detection at 254 nm. Analytes were extracted from acidified samples with tert.-butylmethyl ether and separated with an RP-18 column (150 mm x 3 mm I.D., 5 microns particle size) with a mixture of 0.01 M potassium phosphate and methanol (70:30, v/v) at pH 3.1. The method proved to have the validation required for pharmacokinetic investigations in animals and humans.
Assuntos
Benzoatos/farmacocinética , Tiofenos/farmacocinética , Animais , Aspirina/farmacocinética , Benzoatos/sangue , Benzoatos/urina , Cromatografia Líquida , Feminino , Concentração de Íons de Hidrogênio , Masculino , Naproxeno/sangue , Naproxeno/urina , Ratos , Ratos Endogâmicos , Salicilatos/sangue , Salicilatos/farmacocinética , Salicilatos/urina , Ácido Salicílico , Espectrofotometria Ultravioleta , Tiofenos/sangue , Tiofenos/urina , Distribuição TecidualRESUMO
2-[2-Thiophenecarboxythio]-N-[dihydro-2-(3H)-thiophenone-3-y l]- propionamide (MR 889) was administered orally to rats in order to investigate its pharmacokinetics. 1-2 h after the administration, MR 889 was detected as unchanged compound in plasma only in traces whereas some catabolites, i.e. 2-thiophene carboxylic acid and its glycinate were detected with a tmax of 2 h. The thiolic component of MR 889 induced an evident and sustained increase of total sulfhydryl groups in plasma (tmax 2 h), tissues and urine. Relevant concentrations of 2-thiophene carboxylic acid were found in small intestine and gastric wall followed by liver, lungs and kidneys. The thiolic component also increased, mainly in liver and lungs followed by small intestine and gastric wall. Homocysteine thiolactone S-methyl thiolactamide was identified as a minor metabolite of MR 889.
Assuntos
Inibidores de Proteases/farmacocinética , Tiofenos/farmacocinética , Administração Oral , Animais , Biotransformação , Cromatografia Líquida de Alta Pressão , Fezes/química , Injeções Intraperitoneais , Absorção Intestinal , Masculino , Inibidores de Proteases/metabolismo , Ratos , Ratos Endogâmicos , Estereoisomerismo , Compostos de Sulfidrila/sangue , Tiofenos/metabolismo , Distribuição TecidualRESUMO
The cyclic thiolic compound 2-[3-thiophencarboxythio]-N-[dihydro-2(3H)-thiophenone-3-il] - propionamide (MR889) was investigated as inhibitor of endopeptidases. The activity of bovine pancreatic alpha-chymotrypsin, human leukocyte cathepsin G and rabbit liver cathepsin B was not affected by MR889, whereas porcine pancreatic elastase and human leukocyte elastase were inhibited. The kinetic mechanism of inhibition of human leukocyte elastase was of the reversible, slow-binding, fully competitive type. The rate constants for complex formation between MR889 and leukocyte elastase, determined by pre-steady-state kinetic analysis in the presence of a tetrapeptide substrate at 37 degrees and pH 7.40, were kon = 2363 +/- 15 M-1 sec-1, koff = 3.01 +/- 0.34 x 10(-3) sec-1. The inhibition equilibrium constant was Ki = koff/kon = 1.27 +/- 0.15 microM. Ki, calculated from steady-state kinetic experiments, was 1.38 microM. MR889 also inhibited the elastolytic activity of leukocyte elastase, as determined with insoluble elastin as the substrate.
Assuntos
Elastase Pancreática/antagonistas & inibidores , Inibidores de Proteases/farmacologia , Tiofenos/farmacologia , Catepsina B/antagonistas & inibidores , Catepsina G , Catepsinas/antagonistas & inibidores , Quimotripsina/antagonistas & inibidores , Humanos , Técnicas In Vitro , Cinética , Elastase de Leucócito , Serina Endopeptidases , Especificidade por SubstratoRESUMO
The relationship between extracellular calcium concentration and isovolumic systolic pressure developed by left ventricles was studied in Langendorff-perfused rat hearts. At diastolic pressure lower than 15 mmHg the isovolumic systolic pressure increased when external calcium was changed from 0.5 to 1.25 mM. Pressure stabilized when external calcium was increased to 3.5 mM but then declined at 5 mM Ca2+. At higher diastolic pressures (20 and 25 mmHg) systolic pressure increased only up to 1.25 mM Ca2+, and declined with further increases in external calcium concentration. This behavior is probably related to "calcium overload" of the preparations at external calcium concentrations greater than 3.5 mM associated with a decreased perfusion pressure gradient at higher diastolic pressures.
Assuntos
Pressão Sanguínea , Cálcio/metabolismo , Contração Miocárdica , Animais , Feminino , Masculino , Ratos , Ratos Endogâmicos , Função VentricularRESUMO
The relationship between extracelular calcium concentration and isovolumic systolic pressure developed by left ventricles was studied in Langendorff-perfused rat hearts. At diastolic pressure lower than 15 mmHg the isovolumic systolic pressure increased when external calcium was changed from 0.5 to 1.25 mM. Pressure stabilized when external calcium was increased to 3.5 mM but then declined at 5 mM Ca**2+. At higher diastolic pressures (20 and 25 mmHg) systolic pressure increased only up to 1.25 mM Ca**2+, and declined with further increases in external calcium concentration. This behavior is probably related to "calcium overload" of the preparations at external calcium concentrations greater than 3.5 mM associated with a decreased perfusion pressure gradient at higher diastolic pressures
