Biotransformation studies of prednisone using human intestinal bacteria; part I: aerobic incubation

Several corticosteroids are commonly used for treatment of conditions associated with inflammatory disorders and as immune modulators. Specifically in cases of ulcerative colitis and the related inflammatory bowel syndromes, these therapeutic agents are administered rectally and are subjected to several intestinal micro floras. The present study aimed to investigate the effect of human intestinal bacterial [HIB] aerobic incubation on prednisone 1 as a model for corticosteroids. Within 96 hours, 1 was mostly transformed by HIB in vitro to various metabolites, which could be separated by column chromatography into two fractions. The first eluted fraction. A was found to contain the major metabolite adrenosterone androst-4-ene3, 11,1 7-trione m[1], whereas fraction B contains metabolite m[2] which was identified by chiral HPLC as a mixture of androst-l,4-diene-3, II, 1 7-trione enantiomers. The structures of metabolites m[1]and m[2] were identified and characterized by spectroscopic techniques, including 2D-NMR and mass spectrometry. Time course of biotransformation of 1 by HIB was also studied

Activated ester-carbamate type redox chemical delivery system for improved specific delivery of dopamine to the brain

Enhanced central delivery of dopamine [DA] was proposed by application of a dihydropyridine <=> pyridinium salt redox system. the dihydronicotinate moiety was chemically attached to the amino group of dopamine [DA] by a substitued carbamate linkage.this was achieved by acylation of the amino group of DA with chloroethyl chloroformate, followed by condensation with sodium nicotinate under mild conditions. The product was selectively N-alkylated at the pyridine ring and subjected to regioselective reduction to the corresponding 1,4-dihydropyridine derivative. In vitro stability of the prepared chemical delivery system [Dopamine -Chemical Delivery system; DA-CDS2] was studied in phosphate buffer at physiological pH 7.4,acidic as well as at alkaline pH values. Oxidation studies showed that dihydronicotinate is readily converted to the quaternary salt, both chemically and enzymatically. In vivo changes is spontaneous locomotion studies in rat indicated that the new system exerted a significant biological activity

Niridazole prodrugs: Synthesis, characterization and hydrolysis kinetics of some N-acyloxymethyl niridazoles

A series of 3-acyloxymethylniridazole have been prepared by acylation of 3-hydroxymethylniridazole. The structure of the prepared compounds was confirmed by IR, 1 H-NMR and elemental analysis. They were also evaluated with regard to water solubility, partition coefficient, hydrolysis kinetics and enzymatic cleavage. The water solubility of some of these prodrugs was markedly improved over that of niridazole. Meanwhile, their lipid solubility was comparable with that of the parent drug. In vitro chemical stability of all the synthesized prodrugs was studied at different pH-values, as well as in 80% human plasma for one of themas representative example to assess its cleavage enzymatically to the parent drug, in both cases a strict first- order hydrolysis kinetics was observed. The t 1/2 values varied with variation of the acyl-moiety. The obtained results show as significant improvement in physicochemical properties of the products relative to the parent drug