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PubMed1997

Red blood cells participate in the metabolic clearance of catecholamines in the rat.

The aim of the present study was to investigate the possible role of erythrocytes in the metabolic clearance of catecholamines (CAs) in the rat. Intravenous infusion of exogenous CAs (dopamine -DA-, norepinephrine -NE-, or epinephrine -Epi-) was carried out at increasing doses to cover a range of plasma concentrations from the lower to the upper physiological and to pharmacological levels. Whatever the mechanism(s) underlying the CAs erythrocyte/plasma balance: 1. it seemed more efficient at lower concentrations of CAs; 2. it reached an apparent plateau where plasma and erythrocyte concentrations were not statistically different; 3. finally, saturation was suggested when further increase in plasma concentration was associated with a lower response in erythrocytes. This series of experiments confirms previous reported results with human erythrocytes and suggests that rat erythrocytes could transport CAs from their sites of release to their sites of elimination. In a second series of experiments, the intra-erythrocyte metabolism of CAs was investigated. DA was strikingly increased in plasma and in erythrocytes 2 hours after 1,2-dimethyl-3-hydroxy-4-pyridone (CP20), 100 mg/kg i.p., known to inhibit catechol-O-methyl transferase. Our data demonstrate an increase in glucuro-conjugated DA in vivo (24 hours after CP20 injection) as well as in vitro (3 hours incubation at 37 degrees C), suggesting activation of the glucuroconjugating pathway. Increased glucuroconjugated DA after in vitro incubation demonstrates intra-erythrocyte synthesis while increased concentration in Ringer-Hepes medium demonstrates an inside-out transport of glucuro-conjugate. These data are the first evidence in favour of an intra-erythrocyte glucuro-conjugation of CAs in the rat.

Animals↗
PubMed1987

1,2-Dimethyl-3-hydroxypyrid-4-one, an orally active chelator for treatment of iron overload.

Subcutaneous desferrioxamine, though effective in preventing or reducing iron overload in transfusion-dependent refractory anaemia, is expensive and inconvenient. One potentially cheaper and orally active alternative is 1,2-dimethyl-3-hydroxypyrid-4-one (L1). This drug has been tested in three multiply transfused patients with myelodysplasia. Gelatin capsules were taken at doses ranging from 0.5 g to 3.0 g. Urinary iron excretion increased substantially in all three patients and in the one tested was equal to that achieved with comparable doses of subcutaneous desferrioxamine. The amounts of iron excreted were related to the dose of L1 administered and the iron load of the patients. The urinary excretion of zinc, magnesium, and calcium did not increase, and the drug was well tolerated.

Administration, Oral↗
PubMed2000

Structural study of the interaction of vanadate with the ligand 1,2-dimethyl-3-hydroxy-4-pyridinone (Hdmpp) in aqueous solution.

The interaction of vanadate with the ligand 1,2-dimethyl-3-hydroxy-4-pyridinone (Hdmpp) was studied in aqueous solution using a combination of multinuclear NMR and EPR spectroscopies, as well as potentiometry and cyclic voltammetry. The different species in solution were identified and characterized, and their pKa values and stability constants determined. The vanadium complexes formed in solution are strongly dependent on media composition (ionic strength, presence of buffer), pH and metal-to-ligand ratio (M:L). Two major species--V(V)/dmpp and V(V)/(dmpp)2--are formed in a 140 mM NaCl solution within the pH range 4.5 to 9.0, when M:L = 1:2. In the presence of excess ligand (M:L < or = 1:5), only the 1:2 complex is present, and at pH < 4 paramagnetic species are detected by EPR in solution, thus indicating a reducing capacity of the ligand. Cyclic voltammetry shows that redox processes in solution are not just electron transfer, but are accompanied by chemical reactions. The pK, values and stability constants were determined both by 51V NMR spectroscopy and potentiometry. The present results have a particular interest in the understanding of the aqueous solution chemistry in aerobic conditions of bis(1,2-dimethyl-3-hydroxy-4-pyridinonato) oxovanadium(IV) complex, VO(dmpp)2, a vanadium compound with potential insulin-mimetic properties.

Deferiprone↗
PubMed1999

Aluminum speciation studies in biological fluids. Part 5. A quantitative investigation of A1(III) complex equilibria with desferrioxamine, 2,3-dihydroxybenzoic acid, Tiron, CP20 (L1), and CP94 under physiological conditions, and computer-aided assessment of the aluminum-mobilizing capacities of these ligands in vivo.

While the involvement of environmental aluminum toxicity in the advent of senile dementias is still debated, acute aluminum toxicity of iatrogenic origin is well documented. So far, the only treatment available against it has been desferrioxamine (DFO), which induces major side effects. New drugs are thus highly desirable, and possible DFO substitutes have already been considered through various techniques. An important test for such new drugs is to assess their A1-mobilizing capacity in vivo. This can be done by computer-aided speciation provided formation constants for the corresponding A1(III) complexes are known beforehand. The present work reports an investigation of A1(III) complex equilibria with five sequestering ligands including DFO, and predicts the respective capacities of these to mobilize aluminum in vivo under normal and inflammatory conditions.

1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium ↗
PubMed1998

Iron removal from monoferric human serum transferrins by 1, 2-dimethyl-3-hydroxypyridin-4-one, 1-hydroxypyridin-2-one and acetohydroxamic acid.

The kinetics of iron removal from both forms of human serum monoferric transferrin by three ligands, 1, 2-dimethyl-3-hydroxypyridin-4-one (L1), 1-hydroxypyridin-2-one and acetohydroxamic acid, have been evaluated at pH 7.4 and 25.0 degreesC. In almost all cases the rate of iron removal follows simple saturation kinetics with respect to the ligand concentration. No spectroscopically distinct intermediates are observed during the iron removal reaction, which is consistent with a mechanism in which the rate-limiting step in iron removal is a protein conformational change. In the presence of chloride or perchlorate, most systems continue to follow simple saturation kinetics, but with significantly different kmax values. Chloride accelerates iron release from both transferrin binding sites, while perchlorate accelerates iron release from the C-terminal site but retards iron release from the N-terminal site. When the hydrochloride salt of L1 is used to prepare the L1 stock solution, the allosteric effect of the chloride produces a continuing increase in the rate of iron removal with increasing ligand concentration, so that one no longer observes simple saturation kinetics. A least squares fit of kobs vs. the ligand concentration for L1.HCl shows that the allosteric effect of the chloride not only enhances the first-order term for iron removal but also doubles the apparent kmax for the saturation term. This supports the view that allosteric binding of anionic ligands contributes to the observed variation in kmax among different ligands. A detailed description of this allosteric effect is not yet possible because the effect varies significantly from system to system, depending upon the specific anion that is binding at the allosteric site, the ligand that is used to remove the iron, and the transferrin lobe from which iron is removed.

Allosteric Regulation↗