Search PubMed⌕ Search

Biomedical subjects

R Maffei Facino

Publications and source records attributed to R Maffei Facino.

At least 19 recordsLinked to original sources
PubMed2006

Antioxidant activity of polyphenols from solid olive residues of c.v. Coratina.

The antioxidant profile of extracts from solid olive residue (SOR) of c.v. Coratina, a cultivar widely diffused in the south of Italy, using both cell-free and cell-based experimental models, was investigated. A total hydroalcoholic extract (polyphenols content 19.7%) and a purified extract (Oleaselecttrade mark) (polyphenols content 35.1%) were tested for their ability to quench the stable free radical DPPH, the peroxyl radicals (ORAC assay), by monitoring the loss in fluorescence of R-phycoerythrin induced by the peroxyl radical generator AAPH and their ability to inhibit the cumene hydroperoxide-induced lysis of rat red blood cells (RBC). The total hydroalcoholic extract showed IC(50) 26.96+/-1.53 microg/ml in the DPPH assay, that 10 microg/ml were equivalent to 2.11+/-0.12 microg/ml Trolox (ORAC assay) and IC(50) 1.7+/-0.20 microg/ml in the RBC hemolysis. The Oleaselect extract was 4 to 5 folds more active than the hydroalcoholic extract in all the experimental models, with IC(50) values of 7.36+/-0.38 microg/ml in the DPPH test and of 0.38+/-0.03 microg/ml in RBC; the antioxidant activity in the ORAC assay was slightly greater than that of Trolox (10 microg/ml equivalent to 11.45+/-0.40 microg/ml). The scavenging effect of the extract in the ORAC assay was compared to that of verbascoside (the main polyphenol component) and of caffeic acid (the basic constituent of verbascoside): the results indicate that caffeic acid (10 microg/ml equivalent to 35.70+/-2.95 microg/ml Trolox) is more potent than verbascoside (10 microg/ml equivalent to 15.42+/-1.21 microg/ml Trolox) in entrapping peroxyl radicals. Finally the antioxidant activity of the Oleaselect extract was confirmed in human umbilical endothelial cells (EC) exposed to the site-specific peroxyl radical inducer AAPH, where a massive lipid peroxidation process (marker the fluorescence probe BODIPY) takes place, paralleled by a marked loss of cell viability (calcein assay). The purified extract (1-20 microg/ml) pre-incubated with EC for 1 h dose-dependently inhibited both the lipid-peroxidation damage and cell death. Taking into account the total polyphenol content, these results clearly indicate a greater antioxidant activity for the purified extract, due to a cooperative antioxidant interaction among its polyphenol constituents.

Amidines↗
PubMed2000

UVB-induced hemolysis of rat erythrocytes: protective effect of procyanidins from grape seeds.

Besides erythema and sunburn reactions, UVB stress can promote erythrocyte extravasation from skin capillaries and hemolysis, and photosensitized hemoglobin can in turn lead to an overload of free radicals in dermis which exacerbates photodamage. The objective of this study was to investigate in rat erythrocytes (RBC) the pattern of events leading to membrane peroxidation and hemolysis following UVB insult (1.5-8.5 J/cm2), and the protective action of grape seed procyanidins. UVB causes a dramatic dose-dependent decrease of intracellular glutathione (paralleled by the formation of pro-oxidant ferryl-hemoglobin), of intramembrane vitamin E and of membrane fluidity, then a rise of conjugated dienes (CD), and thiobarbituric acid-reactive substances (TBARS) and finally a strong hemolytic effect. Procyanidins prevent membrane peroxidation (but not intracellular GSH depletion nor ferryl-hemoglobin formation), with a minimal effective concentration of 0.1 microM (IC50 for TBARS and CD after 120 min UVB exposure: 0.71 microM and 0.56 microM) and dose-dependently delay the onset of hemolysis, by 30 min at 0.1 mciroM, by 90 and 120 min at 0.5 and 1.0 microM. Epigallocatechin-3-O-gallate (EGCG) and catechin, typical constituents of the fraction, were significantly less potent. This since procyanidins (1 microM) inhibit the formation of phospholipid hydroperoxides of the inner (phosphatidylserine, phosphatidylethanolamine) and outer (phosphatidylcholine) layers of the RBC membrane (HPLC analysis), suppress the decrease in membrane fluidity due to lipid and protein thiol oxidation and spare vitamin E from consumption in a dose-dependent manner (0.1-1 microM). Hence procyanidins, preserving membrane phospholipids, since their strong antilipoperoxidant activity, may maintain in vivo the integrity of RBC in sub-epidermal capillaries and effectively counteract in dermis the onset/exacerbation of the UVB-induced skin photodamage.

Animals↗
PubMed1999

Panax ginseng administration in the rat prevents myocardial ischemia-reperfusion damage induced by hyperbaric oxygen: evidence for an antioxidant intervention.

The aim of this work was to investigate in the rat the protective effect of an oral administration (one week) of Panax ginseng (PG) extract (10 mg/ml in drinking water; 1.6 g/kg/day) on myocardial post-ischemic damage induced by hyperbaric oxygen (HBO) and on the loss in functionality of the endothelium in aorta ring preparations. The hearts from control rats (no-HBO and no-HBO-PG), and from rats exposed to HBO and to HBO after PG treatment were isolated and subjected to mild ischemia and then reperfused. HBO greatly worsens the post-ischemic damage in controls, as demonstrated by the rise of left ventricular end diastolic pressure (LVEDP) and coronary perfusion pressure (CPP). PG significantly restrained the increase of LVEDP and CPP in respect to HBO-untreated rats, as well as that of CPP induced by injection of angiotensin II during pre-ischemia. In HBO control rats the reduction of the vasorelaxant effect of acetylcholine on norepinephrine precontracted aortic rings, was markedly recovered by PG; a similar trend was observed in aortic rings challenged with the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (56% recovery). These results strongly indicate that PG prevents the myocardial ischemia/reperfusion damage and the impairment of endothelial functionality induced by reactive oxygen species arising from HBO exposure, through an antioxidant intervention. The in vitro radical scavenging activity of PG seems to be too weak (0.05-0.5 mg/ml) to explain by itself the cardiac and extra-cardiac protective effects, and this suggests a role also for an indirect antioxidant action of the drug (endothelial nitric oxide synthase stimulation).

Administration, Oral↗
PubMed1998

Sparing effect of procyanidins from Vitis vinifera on vitamin E: in vitro studies.

The sparing/recycling effect of a highly purified, high molecular weight fraction of catechin oligomers (procyanidins) from Vitis vinifera seeds on alpha-tocopherol was studied in both homogeneous solution and in heterogeneous phase (phosphatidylcholine liposomes and red blood cells). By HPLC and electron spin resonance (ESR) spectroscopy we evidenced that tocopheroxyl radical, induced by reaction of alpha-tocopherol with the stable radical DPPH (2,2-diphenyl-1-picrylhydrazyl) is recycled by procyanidins. In addition procyanidins significantly and dose-dependently spare vitamin E from consumption (HPLC monitoring) during the autooxidation phase of the HO-induced peroxidation of phosphatidylcholine, by 23% at the lowest concentration (0.5 microM) and by 65.5% at 3 microM. In this membrane model the combination of 0.5 microM procyanidins and 2 microM alpha-tocopherol results in a marked delay in the appearance of conjugated dienes in respect to the single antioxidants (synergistic interaction), while catechin showed to be active only at 5 microM. In red blood cells oxidatively stressed by UVB exposure, procyanidins at 0.1-1.0 microM prevent vitamin E loss, markedly decrease membrane lipid peroxidation, linearly related to the concentration of vitamin E in the membranes, and significantly delay the onset of hemolysis (catechin protects between 5 and 10 microM).

Animals↗
PubMed1997

Hydroxynimesulide, the main metabolite of nimesulide, prevents hydroperoxide/hemoglobin-induced hemolysis of rat erythrocytes.

The protective effect of hydroxynimesulide, the main metabolite of the nonsteroidal antiinflammatory drug nimesulide, on red blood cells (RBCs, 0.2%; 3.5 x 10(7) cell/ml) hemolysis induced by cumene hydroperoxide (CuOOH; 50 microM) was evaluated by turbidimetric and morphological analyses. Hydroxynimesulide inhibits the CuOOH-induced hemolysis in a dose dependent fashion: the protective effect, calculated after 150 min incubation (100% hemolysis in the controls), starts at 1 micron (% hemolysis 85.2 +/- 3.4%) and increases at the higher concentrations (63.5 +/- 3.9% at 5 microM; 43.5 +/- 6.3% at 10 microM; and, 14.5 +/- 4.3% at 20 microM). In addition, in the samples protected with 10 microM and 20 microM, there is a significant delay (30 and 60 min) in the onset of the hemolytic response. Inhibition of hemolysis is the result of protection of RBC membrane integrity, both on lipid (cis-Parinaric acid fluorescence quenching was delayed by 53 +/- 10 sec vs. the controls at 1 micron, by 115 +/- 15 sec at 5 microM, with a lag phase of 240 +/C- 18 sec at 10 microM) and protein constituents, as determined by SDS-PAGE electrophoresis. In hemolysis experiments, the efficacy of hydroxynimesulide is comparable to that of alpha-tocopherol and a cooperative interaction between hydroxynimesulide and alpha-tocopherol (both at 10 microM) has been observed. These results indicate that hydroxynimesulide protects RBC membranes by directly quenching reactive oxygen species generated by hemoglobin/peroxide interaction. Evidence for a direct radical scavenging intervention of the metabolite comes from HPLC studies, which demonstrate a time-dependent consumption of hydroxynimesulide, with the concomitant formation of two main reaction (addition/oxidation) products.

Animals↗
PubMed1995

Differential inhibition of superoxide, hydroxyl and peroxyl radicals by nimesulide and its main metabolite 4-hydroxynimesulide.

The superoxide and hydroxyl radical scavenging activities of nimesulide (CAS 51803-78-2) and its main metabolite 4-hydroxynimesulide (CAS 109032-22-6) were investigated by Electron Spin Resonance (ESR) spectroscopy, with the spin trapping technique. Hydroxynimesulide is a good scavenger of both O2 degrees- (IC50 = 40 mumol/l) and HO degree (IC50 = 54.8 mumol/l) radicals, and its high reactivity towards HO degree was confirmed by the rate constant for reaction with HO degree (K = 8.9 x 10(10) mol-1 l s-1) determined by competition kinetic studies with 5,5-dimethyl-l-pyrroline-N-oxide. Nimesulide, which has been shown by ESR to be inactive as a superoxide quencher, has a rate constant of reaction with HO degree slightly greater than that of its metabolite (3.3 x 10(11) mol-1 l s-1). In the HO degree-induced peroxidation of phosphatidylcholine (PC) liposomes, both compounds act as potent preventive antioxidants, but the HO degree entrapping capacity of the parent drug was again greater than that of hydroxynimesulide (IC50 2.12 vs 3.84 mumol/l). The metabolite is also a potent scavenger of the peroxyl radical (ROO degree) in the propagation phase of PC peroxidation (marker conjugated dienes), with an IC50 = 2.67 mumol/l; at 5 mumol/l it induces a lag time in the decomposition of PC hydroperoxides (PC-OOH) into aldehydic products of 40 h longer than in the controls (markers: conjugated dienes and total carbonyl functions). In PC liposomes, in the presence of preformed PC-OOH, the metabolite prevents PC peroxidation stimulated by 5 mumol/l Fe2+, via the Fenton reaction (marker: conjugated dienes), at the micromolar level (IC50 = 17 mumol/l) through an anti-free radical activity and a free iron chelating mechanism. Hydroxynimesulide in fact interacts with Fe2+ ions, giving rise to a strong complex, with a stability constant (log K) estimated to be around 8/9. In addition, hydroxynimesulide efficiently protects ex vivo synovial fluid lipids from the oxidative stress induced by Fe2+/ascorbate, already at 10 mumol/l (marker: thiobarbituric acid reactive substances). These results provide evidence for strong antioxidant and iron-chelating properties of 4-hydroxynimesulide, which can act synergistically with the specific HO degree scavenging activity of the parent drug in preventing and limiting in vivo the free radical-mediated tissue damage in both acute and chronic inflammatory situations.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1994

Free radicals scavenging action and anti-enzyme activities of procyanidines from Vitis vinifera. A mechanism for their capillary protective action.

The scavenging by procyanidines (polyphenol oligomers from Vitis vinifera seeds, CAS 85594-37-2) of reactive oxygen species (ROS) involved in the onset (HO degrees) and the maintenance of microvascular injury (lipid radicals R degrees, RO degrees, ROO degrees) has been studied in phosphatidylcholine liposomes (PCL), using two different models of free radical generation: a) iron-promoted and b) ultrasound-induced lipid peroxidation. In a) lipid peroxidation was assessed by determination of thiobarbituric acid-reactive substances (TBARS); in b) by determination of conjugated dienes, formation of breakdown carbonyl products (as 2,4-dinitrophenylhydrazones) and loss of native phosphatidylcholine. In the iron-promoted (Fenton-driven) model, procyanidines had a remarkable, dose-dependent antilipoperoxidant activity (IC50 = 2.5 mumol/l), more than one order of magnitude greater than that of the monomeric unit catechin (IC50 = 50 mumol/l), activity which is due, at least in part, to their metal-chelating properties. In the more specific model b), which discriminates between the initiator (hydroxyl radical from water sonolysis) and the propagator species of lipid peroxidation (the peroxyl radical, from autooxidation of C-centered radicals), procyanidines are highly effective in preventing conjugated diene formation in both the induction (IC50 = 0.1 mumol/l) and propagation (IC50 = 0.05 mumol/l) phases (the scavenging effect of alpha-tocopherol was weaker, with IC50 of 1.5 and 1.25 mumol/l). In addition, procyanidines at 0.5 mumol/l markedly delayed the onset of the breakdown phase (48 h), totally inhibiting during this time the formation of degradation products (the lag-time induced by alpha-tocopherol was only of 24 h at 10 mumol/l concentration). The HO degrees entrapping capacity of these compounds was further confirmed by UV studies and by electron spin resonance (ESR) spectroscopy, using DMPO as spin trapper: procyanidines markedly reduced, in a dose-dependent fashion, the signal intensity of the DMPO-OH radical spin adduct (100% inhibition at 40 mumol/l). The results of the second part of this study show that procyanidines, in addition to free radical scavenging action, strongly and non-competitively, inhibit xanthine oxidase activity, the enzyme which triggers the oxy radical cascade (IC50 = 2.4 mumol/l). In addition procyanidines non-competitively inhibit the activities of the proteolytic enzymes collagenase (IC50 = 38 mumol/l) and elastase (IC50 = 4.24 mumol/l) and of the glycosidases hyaluronidase and beta-glucuronidase (IC50 = 80 mumol/l and 1.1 mumol/l), involved in the turnover of the main structural components of the extravascular matrix collagen, elastin and hyaluronic acid.(ABSTRACT TRUNCATED AT 400 WORDS)

Biflavonoids↗
PubMed1993

Antioxidant profile of nimesulide, indomethacin and diclofenac in phosphatidylcholine liposomes (PCL) as membrane model.

An in vitro assay based on the oxidation of phosphatidylcholine liposomes (PCL) with which we can distinguish the anti-HO zero activity from the antilipoperoxidant (R zero, ROO zero, RO zero) has been developed for testing the free-radical-scavenging ability of antiinflammatory drugs. PCL were exposed to a flux of hydroxyl radicals generated by water sonolysis for different periods, and the spontaneous lipid peroxidative phenomenon (propagation and breakdown phases) was followed for the subsequent 24 hours. Lipid peroxidation was assayed by simultaneous measurements of a) conjugated dienes, by UV spectroscopy (absorbance and second derivative at 233 nm), b) loss of lipid substrate (PC), by HPLC, and c) breakdown products (total carbonyl functions as 2,4-dinitrophenylhydrazones). Diclofenac, nimesulide and indomethacin, added to PCL at the starting of the different stages of lipid peroxidation, were tested for their overall and specific anti-radical properties. All the drugs exhibited a remarkable scavenging activity against oxy and lipid radicals, determined as percent inhibition of the formation of conjugated dienes, at concentrations easily attainable in vivo (IC50:diclofenac 2.5 microM, nimesulide 4.92 microM, indomethacin 6.85 microM), diclofenac being the most effective in quenching the R zero and ROO degree species responsible for the propagation phase. By contrast, the antioxidant activity of nimesulide and indomethacin, less potent as alkyl and peroxyl radical scavengers, is due to their ability to restrain the induction phase of the radical chain reaction mediated by hydroxyl radicals (IC50:nimesulide 1.85 microM, indomethacin 3.57 microM).

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1993

Efficacy of glutathione for treatment of fascioliasis. An investigation in the experimentally infested rat.

Liver fluke infection (Fasciola hepatica) depresses the drug-metabolizing capacity of the hepatic mixed function oxidase (MFO) and glucuronosyltransferase (GT) enzyme systems, throughout a free radicals mediated lipid peroxidation process. Glutathione (GSH, CAS 70-18-8) administered chronically (100 mg/kg i.p. once daily for 40 days) to experimentally infested rats from the onset to the maximal development of the infection (40th day), greatly reduced the damage to membrane lipids of the liver tissue (primary event of the disease), as judged by malonic dialdehyde (MDA) content (decreased by 80%) and diene conjugation absorption (delta E 1% value falls from 1.94 to 0.67). As a consequence, serum glutamate-oxaloacetate (GOT) and glutamate-pyruvate (GPT) transaminases levels, liver GSH and phospholipid (PL) contents, cytochrome P-450, NADPH-cytochrome-P-450 reductase and some typical cytochrome P-450-dependent activities (p-nitroanisole O-demethylase, aniline hydroxylase, as well as UDP-glucuronosyltransferase (GT) activity, all markedly affected in the acute stage of the disease, tend to recover to the control values. The efficacy of GSH in preventing the impairment of the hepatic drug metabolizing capacity was also demonstrated by using as substrate the widely employed flukicidal agent nitroxinil (3-iodo-4-hydroxy-5-nitrobenzonitrile). The in vitro cytochrome P-450-dependent nitroxinil detoxification (reduction to 3-iodo-4-hydroxy-5-aminobenzonitrile), drastically impaired in infested animals (-80%), is markedly restored (3-fold increase) in GSH-treated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗
PubMed1990

Antihepatotoxic properties of uridine-diphosphoglucose in liver fluke infection. Experimental fascioliasis in the rat.

The antihepatotoxic properties of uridine-diphosphoglucose (UDPG, Toxepasi) have been evaluated in a well-established model of liver damage, the liver fluke infection (experimental fascioliasis in the rat), which causes a dramatic loss of the microsomal drug-metabolizing monooxygenase (MFO) and glucuronosyltransferase (GT) enzyme systems as a consequence of peroxidative damage to microsomal membrane lipids. Administration of 100 mg/kg UDPG i.p. to the infested rat for the entire course of the infection (40 days) positively affects the parameters reflecting the integrity of the liver cell (serum glutamate-pyruvate, GPT and glutamate-oxaloacetate, GOT, transaminases) and the detoxifying capacity of the liver (cytochrome P-450, cytochrome b5, cytochrome P-450-dependent p-nitroanisole O-demethylase and aniline hydroxylase activities, and the p-nitrophenol glucuronidation) and greatly reduces the lipid peroxidative phenomen in membranes from whole liver (tissue malonic dialdehyde content) and in membranes of the microsomal fraction (conjugated diene absorption). As a consequence of this, the total lipid and phospholipid contents of the liver are restored, there is minimal loss of latency of GT enzyme(s), cytochrome P-450 conversion to cytochrome P-420 is fairly negligible and total liver glutathione content is also restored. Therefore, UDPG restores liver function by protecting the endoplasmic reticulum membranes from the oxidative stress resulting from activation of the CN-insensitive respiratory burst of the phagocytic cells consequent to Fasciola hepatica invasion, migration and growth. It is very likely that UDPG acts as an effective antilipoperoxidative agent through both direct (as demonstrated by our in vitro experiments) and indirect mechanisms (stimulation of the glycolytic pathway, and hence of the reducing equivalents----glutathione----vitamin E supply).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

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 beta-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 beta-oxidation activity. This indicates that tiadenol carboxylic metabolites act as the enzymatic effectors.

Animals↗
PubMed1987

Experimental studies on pharmacology, metabolism and toxicology with tiadenol-disulfoxide. Dissociation of lipid lowering effects and the induction of peroxisomal and microsomal drug-metabolizing enzymes.

The hypolipidemic activity of tiadenol-disulfoxide, the major metabolite of 1,10-bis(hydroxyethylthio)decane (tiadenol, Eulip) in man and in the rat was assessed in various experimental models versus the corresponding activity of tiadenol. Tiadenol-disulfoxide in the normolipidemic rats lowers total serum cholesterol and serum and liver triglycerides in an extent comparable to that of the reference compound. Likewise, it is equally effective as tiadenol in preventing Triton-induced hyperlipidemia and Nath diet induced hypercholesterolemia; in addition tiadenol-disulfoxide is slightly more effective than tiadenol in increasing HDL-cholesterol in hypercholesterolemic rats. At hypolipidemic doses the compound causes no hepatomegaly, no induction of peroxisomal catalase and palmitoyl-CoA oxidase activities, no smooth endoplasmic reticulum proliferation and no induction of microsomal cytochrome P-450 and of cytochrome P-450 dependent enzyme activities: aminopyrine (aminophenazone) N-demethylase, aniline hydroxylase, zoxazolamine hydroxylase and hexobarbital oxidase. At the suprapharmacological dose of 300 mg/kg tiadenol-disulfoxide, if compared to the reference compound, shows a generally lower order of toxicity on these hepatic parameters. Orally administered tiadenol-disulfoxide is well absorbed by the gastrointestinal tract and is eliminated in urine at 45% of the dose in unchanged form, and the remaining being: glucuron-conjugated tiadenol-disulfoxide (10%), S-oxidized metabolites (15%) and sulfoxidized carboxylic metabolites (15%). The compound is well tolerated both in mice and rats. The results of this comparative study demonstrate that: 1. tiadenol-disulfoxide is a substance with promising hypolipidemic properties; 2. tiadenol-disulfoxide is largely responsible for the hypolipidemic activity of tiadenol; 3. hepatomegaly consequent to tiadenol administration is the consequence of the response of the liver cell to the increased functional demand of the mixed function oxidase (MFO) system involved in the metabolism of the drug; 4. peroxisomal enzyme activities induction observed with both drugs at non-pharmacological doses does not play any role in their hypolipidemic action and is not associated with hepatomegaly.

Animals↗
PubMed1986

A rapid method for the simultaneous detection by collisionally activated dissociation mass-analysed ion kinetic energy spectrometry of parts per trillion of diethylstilbestrol, zeranol and trenbolone in plasma and edible tissues of cattle.

The current methods for the control of the illegal use of anabolics in cattle breeding are far from satisfactory in terms of specificity and sensitivity. Here we describe a method for the simultaneous detection of diethylstilbestrol, zeranol and trenbolone in plasma and edible cattle tissues. The method is rapid (total analysis time 30 min), specific and sensitive (ppt level). The technique employed is a tandem mass spectrometric method: collisionally activated decomposition mass-analysed ion kinetic energy (CAD MIKE) spectrometry. Detection involves the injection of the crude ethanol extracts of plasma and tissues and selection/collision of molecular ions of each targeted compound. Confirmation of the presence of particular compounds is made by matching the complete CAD spectra so obtained with those of the pure compounds.

Animals↗
PubMed1986

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.

Adult↗