Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 5 de 5
Filter
Add more filters










Database
Language
Publication year range
1.
Biochem Pharmacol ; 218: 115867, 2023 12.
Article in English | MEDLINE | ID: mdl-37866801

ABSTRACT

Transporter-mediated drug-drug interactions (DDIs) are assessed using probe drugs and in vitro and in vivo models during drug development. The utility of endogenous metabolites as transporter biomarkers is emerging for prediction of DDIs during early phases of clinical trials. Endogenous metabolites such as pyridoxic acid and kynurenic acid have shown potential to predict DDIs mediated by organic anion transporters (OAT1 and OAT3). However, these metabolites have not been assessed in rats as potential transporter biomarkers. We carried out a rat pharmacokinetic DDI study using probenecid and furosemide as OAT inhibitor and substrate, respectively. Probenecid administration led to a 3.8-fold increase in the blood concentrations and a 3-fold decrease in renal clearance of furosemide. High inter-individual and intra-day variability in pyridoxic acid and kynurenic acid, and no or moderate effect of probenecid administration on these metabolites suggest their limited utility for prediction of Oat-mediated DDI in rats. Therefore, rat blood and urine samples were further analysed using untargeted metabolomics. Twenty-one m/z features (out of >8000 detected features) were identified as putative biomarkers of rat Oat1 and Oat3 using a robust biomarker qualification approach. These m/z features belong to metabolic pathways such as fatty acid analogues, peptides, prostaglandin analogues, bile acid derivatives, flavonoids, phytoconstituents, and steroids, and can be used as a panel to decrease variability caused by processes other than Oats. When validated, these putative biomarkers will be useful in predicting DDIs caused by Oats in rats.


Subject(s)
Organic Anion Transporters , Rats , Animals , Organic Anion Transporters/metabolism , Probenecid/pharmacology , Probenecid/metabolism , Organic Anion Transporters, Sodium-Independent/metabolism , Renal Elimination , Furosemide/pharmacology , Furosemide/metabolism , Organic Anion Transport Protein 1/metabolism , Kynurenic Acid/metabolism , Kynurenic Acid/pharmacology , Pyridoxic Acid/metabolism , Pyridoxic Acid/pharmacology , Drug Interactions , Biomarkers/metabolism , Kidney/metabolism
2.
J Dairy Sci ; 105(11): 8650-8663, 2022 Nov.
Article in English | MEDLINE | ID: mdl-36175222

ABSTRACT

The purpose of this study was to evaluate the effect of 6 different feeding systems (based on corn silage as the main ingredient) on the chemical composition of milk and to highlight the potential of untargeted metabolomics to find discriminant marker compounds of different nutritional strategies. Interestingly, the multivariate statistical analysis discriminated milk samples mainly according to the high-moisture ear corn (HMC) included in the diet formulation. Overall, the most discriminant compounds, identified as a function of the HMC, belonged to AA (10 compounds), peptides (71 compounds), pyrimidines (38 compounds), purines (15 compounds), and pyridines (14 compounds). The discriminant milk metabolites were found to significantly explain the metabolic pathways of pyrimidines and vitamin B6. Interestingly, pathway analyses revealed that the inclusion of HMC in the diet formulation strongly affected the pyrimidine metabolism in milk, determining a significant up-accumulation of pyrimidine degradation products, such as 3-ureidopropionic acid, 3-ureidoisobutyric acid, and 3-aminoisobutyric acid. Also, some pyrimidine intermediates (such as l-aspartic acid, N-carbamoyl-l-aspartic acid, and orotic acid) were found to possess a high discrimination degree. Additionally, our findings suggested that the inclusion of alfalfa silage in the diet formulation was potentially correlated with the vitamin B6 metabolism in milk, being 4-pyridoxic acid (a pyridoxal phosphate degradation product) the most significant and up-accumulated compound. Taken together, the accumulation trends of different marker compounds revealed that both pyrimidine intermediates and degradation products are potential marker compounds of HMC-based diets, likely involving a complex metabolism of microbial nitrogen based on total splanchnic fluxes from the rumen to mammary gland in dairy cows. Also, our findings highlight the potential of untargeted metabolomics in both foodomics and foodomics-based studies involving dairy products.


Subject(s)
Milk , Silage , Cattle , Female , Animals , Milk/chemistry , Zea mays/metabolism , Orotic Acid/analysis , Aspartic Acid/analysis , Aspartic Acid/metabolism , Aspartic Acid/pharmacology , Pyridoxal Phosphate/analysis , Pyridoxal Phosphate/metabolism , Pyridoxal Phosphate/pharmacology , Pyridoxic Acid/analysis , Pyridoxic Acid/metabolism , Pyridoxic Acid/pharmacology , Lactation , Fermentation , Rumen/metabolism , Pyrimidines/analysis , Pyrimidines/metabolism , Pyrimidines/pharmacology , Medicago sativa/metabolism , Diet/veterinary , Nitrogen/metabolism , Metabolome , Purines , Vitamins/analysis
3.
FASEB J ; 22(3): 890-7, 2008 Mar.
Article in English | MEDLINE | ID: mdl-17965265

ABSTRACT

Histamine, a biogenic amine with important biological functions, is produced from histidine by histidine decarboxylase (HDC), a pyridoxal 5'-phosphate-dependent enzyme. HDC is thus a potential target to attenuate histamine production in certain pathological states. Targeting mammalian HDC with novel inhibitors and elucidating the structural basis of their specificity for HDC are challenging tasks, because the three-dimensional structure of mammalian HDC is still unknown. In the present study, we designed, synthesized, and tested potentially membrane-permeable pyridoxyl-substrate conjugates as inhibitors for human (h) HDC and modeled an active site of hHDC, which is compatible with the experimental data. The most potent inhibitory compound among nine tested structural variants was the pyridoxyl-histidine methyl ester conjugate (PHME), indicating that the binding site of hHDC does not tolerate groups other than the imidazole side chain of histidine. PHME inhibited 60% of the fraction of 12-O-tetradecanoylphorbol-13-acetate-induced newly synthesized HDC in human HMC-1 cells at 200 microM and was also inhibitory in cell extracts. The proposed model of hHDC, containing phosphopyridoxyl-histidine in the active site, revealed the binding specificity of HDC toward its substrate and the structure-activity relationship of the designed and investigated compounds.


Subject(s)
Coenzymes/chemistry , Drug Design , Histidine Decarboxylase/antagonists & inhibitors , Histidine Decarboxylase/chemistry , Histidine/analogs & derivatives , Models, Biological , Pyridoxic Acid/analogs & derivatives , Amino Acid Sequence , Animals , Binding Sites/drug effects , Cell Line, Tumor , Cells, Cultured , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Histidine/chemical synthesis , Histidine/chemistry , Histidine/pharmacology , Humans , Molecular Sequence Data , Molecular Structure , Pyridoxic Acid/chemical synthesis , Pyridoxic Acid/chemistry , Pyridoxic Acid/pharmacology , Rats , Sequence Alignment , Structure-Activity Relationship , Swine
4.
Resuscitation ; 7(2): 127-34, 1979.
Article in English | MEDLINE | ID: mdl-542728

ABSTRACT

Pyridoxylase at a concentration of 0.6 mmol/kg body weight injected intraperitoneally in rats, increased the resistance of animals to severe hypoxia (O2:3.2%; N2; 96.,%). The electrocorticogram (ECoG) was used to indicate the effectiveness of the drug in lowering the delay of electrographic silence, in 19 control rats and 12 pretreated rats. The ECoG was also recorded period under pure oxygen. In pretreated rats, the ECoG records became flat in a mean time of 551 s, compared with 269 s in the control group. The latent periods of successive steps during cerebral anoxia were significantly delayed in pyridoxylate-pretreated rats subjected to hypoxia. During the recovery period, pyridoxylate improved the recovery of the normal ECoG, particularly when values were expressed as a function of the duration of the hypoxic period. These findings are in good agreement with the significant protection afforded by pyridoxylate on the cerebral rate of energy-rich phosphate bond utilization during hypoxia studied in a separate work.


Subject(s)
Brain/physiopathology , Hypoxia, Brain/physiopathology , Isonicotinic Acids/pharmacology , Pyridoxic Acid/pharmacology , Animals , Electrocardiography , Heart Rate , Hypoxia/prevention & control , Male , Rats
5.
Resuscitation ; 7(2): 135-44, 1979.
Article in English | MEDLINE | ID: mdl-542729

ABSTRACT

Pyridoxine (1-8 mmol/l) did not change significantly the cerebral oxygen nor the hypoxic or ischaemic degradation of phosphocreatine and ATP. Glyoxylic acid (1-8 mmol/l), an inhibitor of the citric acid cycle, depressed the electrically stimulated oxygen uptake of brain slices to a lesser extent than did pyridoxylate. Moreover, at concentrations of 0.66 mmol/l, pyridoxylate predominantly delayed the hypoxic or the ischaemic breakdown of creatine phosphate and of ATP compared with glyoxylic acid (0.66 mmol/l). These findings paralleled clearly the prominent hypoxic and post-hypoxic protection afforded by pyridoxylate upon rat brain electrogenesis, reported in the preceding paper.


Subject(s)
Brain Ischemia/metabolism , Cerebral Cortex/metabolism , Glyoxylates/pharmacology , Hypoxia, Brain/metabolism , Isonicotinic Acids/pharmacology , Oxygen/metabolism , Pyridoxic Acid/pharmacology , Pyridoxine/pharmacology , Adenosine Triphosphate/metabolism , Animals , Electric Stimulation , Lactates/metabolism , Phosphates/metabolism , Phosphocreatine/metabolism , Rats
SELECTION OF CITATIONS
SEARCH DETAIL
...