Carboxylic metabolites of tiadenol as "proximate" inducers of hepatic peroxisomal beta-oxidation activity

Chronic exposure of rats to the hypolipidemic agent tiadenol causes a dramatic dose-dependent increase of peroxisomal \u3b2-oxidation activity. To elucidate which metabolite of the drug is the "proximate" inducer (tiadenol is eliminated completely in metabolized form after acute administration) we investigated the qualitative and quantitative metabolic profile of the drug at different doses (50, 150, 300 mg/Kg in two-weeks chronically treated rats, in parallel to that of a model compound, tiadenol-disulfoxide, a weak inducer of palmitoyl-CoA oxidation activity. No changes in the biodisposition of tiadenol (and tiadenol-disulfoxide) were found following chronic treatment for all the doses tested. For both the compounds a strict correlation was evidenced between the extent of formation of carboxylic metabolites and their inductive potencies on peroxisomal \u3b2-oxidation activity. This indicates that tiadenol carboxylic metabolites act as the enzymatic effectors

METABOLISM OF THE HYPOLIPIDEMIC AGENT TIADENOL IN MAN AND IN THE RAT

The metabolism of the hypolipidemic agent 1,10-bis(hydroxyethylthio)decane (tiadenol, Eulip) has been studied in vivo in man and in the rat and in vitro in the rat. Following oral administration, in both species tiadenol was completely absorbed, extensively metabolized by the liver and more than 95% of the dose was eliminated in this form via kidneys within 48 h. Insignificant was the excretion of the unchanged drug in urine (approximately 1%) as well as that of its metabolites in the feces. 8 metabolites were isolated from human or rat urine and their structures were elucidated by means of electron impact, field desorption and positive and negative fast atom bombardment mass spectrometry. Both in man and in the rat the main metabolic pathway was the oxidation of the thioether sulfur, followed by oxidation or conjugation of the primary alcohol group(s). The urinary excretion of S-oxidized metabolites and sulfoxidized carboxylic metabolites accounted for 75% of the dose and that of S-oxidized conjugated metabolites for 20%. Rat in vitro studies showed that hepatic microsomal cytochrome P-450-dependent monooxygenase catalyzes the S-oxidative pathway, which governs the in vivo elimination of the drug in both species. Thus cytochrome P-450 is the key enzyme in the hepatic detoxification of tiadenol

Dose-response decrease in plasma tryptophan and brain tryptophan and serotonin after tryptophan-free amino acid mixtures in rats

Rats fasted 15 hours were treated p.o. with increasing amounts (660 and 1320 mg/kg body weight) of a mixture containing a fixed proportion of seven essential amino acids (L-phenylalanine 13.6%, L-leucine 6.0%, L-isoleucine 12.1%, L-methionine 12.1%, L-lysine 30.3%, L-threonine 10.6%, L-valine 15.2%) and lacking tryptophan. The mixtures produced a dose-response decrease of free (by 34% after the lower dose and by 58% after the higher dose of the mixture) and total (by 10 and 31%) plasma tryptophan and of brain tryptophan (by 38 and 65%), serotonin (by 17 and 41%) and 5-hydroxyindole acetic acid (by 21 and 49%). The mechanisms of these changes are discussed

ANALYSIS OF TIADENOL IN HUMAN-PLASMA BY CAPILLARY GAS-CHROMATOGRAPHY WITH ELECTRON-CAPTURE DETECTION

A sensitive and specific method for the quantitative determination of tiadenol in human plasma is described. After addition of the internal standard, both compounds were quantitatively extracted into chloroform and then derivatized with heptafluorobutyric anhydride (the structures of both derivatives were confirmed by electron impact mass spectrometry). Quantitation was achieved by capillary gas chromatography, using a 63 Ni-electron capture detector. Linearity was observed in the concentration range 5-100 ng ml-1 and the minimum concentration of tiadenol detectable in plasma was 2.0 ng ml-1. The method was successfully applied to plasma specimens collected from healthy human volunteers following a single oral administration of 800 mg of tiadenol

5-Aminolevulinic acid synthetase induction: inhibitory effect exerted by administration of uridine diphosphate glucose.

Journal Articleinfo:eu-repo/semantics/publishe

"In vitro" metabolism of bezafibrate by rat liver

The metabolism of Bezafibrate, a new lipid lowering drug, was studied in vitro using rat liver subcellular fractions as enzymes source. The drug is metabolized in rat liver microsomes through C-oxidation by a cytochrome P-450 mediated process to hydroxy-Bezafibrate. The extent of hydroxy-Bezafibrate formation is limited, because of the type of Bezafibrate interaction with, and its binding parameters to rat liver cytochrome P-450. The mechanism of hydroxy-Bezafibrate formation by rat liver microsomal cytochrome P-450 is discussed