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1.
J Biol Chem ; 276(19): 15823-31, 2001 May 11.
Article in English | MEDLINE | ID: mdl-11278668

ABSTRACT

Selenoprotein P is a plasma protein that has oxidant defense properties. It binds to heparin at pH 7.0, but most of it becomes unbound as the pH is raised to 8.5. This unusual heparin binding behavior was investigated by chemical modification of the basic amino acids of the protein. Diethylpyrocarbonate (DEPC) treatment of the protein abolished its binding to heparin. DEPC and [(14)C]DEPC modification, coupled with amino acid sequencing and matrix-assisted laser desorption ionization-time of flight mass spectrometry of peptides, identified several peptides in which histidine and lysine residues had been modified by DEPC. Two peptides from one region (residues 80-95) were identified by both methods. Moreover, the two peptides that constituted this sequence bound to heparin. Finally, when DEPC modification of the protein was carried out in the presence of heparin, these two peptides did not become modified by DEPC. Based on these results, the heparin-binding region of the protein sequence was identified as KHAHLKKQVSDHIAVY. Two other peptides (residues 178-189 and 194-234) that contain histidine-rich sequences met some but not all of the criteria of heparin-binding sites, and it is possible that they and the histidine-rich sequence between them bind to heparin under some conditions. The present results indicate that histidine is a constituent of the heparin-binding site of selenoprotein P. The presence of histidine, the pK(a) of which is 7.0, explains the release of selenoprotein P from heparin binding as pH rises above 7.0. It can be speculated that this property would lead to increased binding of selenoprotein P in tissue regions that have low pH.


Subject(s)
Heparin/metabolism , Histidine , Lysine , Proteins/chemistry , Proteins/metabolism , Amino Acid Sequence , Animals , Binding Sites , Carbon Radioisotopes , Chromatography, Affinity , Chromatography, High Pressure Liquid , Diethyl Pyrocarbonate/pharmacokinetics , Diethyl Pyrocarbonate/pharmacology , Hydrogen-Ion Concentration , Molecular Sequence Data , Peptide Fragments/chemistry , Proteins/isolation & purification , Rats , Selenoprotein P , Selenoproteins , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
2.
Biopharm Drug Dispos ; 16(3): 201-10, 1995 Apr.
Article in English | MEDLINE | ID: mdl-7787132

ABSTRACT

The pharmacokinetics of ibuprofen diethylcarbonate (ibudice) and naproxen diethythylcarbonate (napdice), two new diethylcarbonate prodrugs of ibuprofen and naproxen, was investigated in dogs. The rationale for the development of ibudice and napdice was that esterification of the carboxylic moiety of the parent compounds would suppress gastrotoxicity without adversely affecting their anti-inflammatory activity. In addition the biotransformation of the prodrugs to the parent compounds may be utilized to achieve rate and time controlled drug delivery of the active entities. Following oral administration the diethylcarbonate esters were rapidly biotransformed to the parent compounds and no ibudice or napdice was detected in the plasma. The relative bioavailability of ibuprofen and naproxen, following oral administration of ibudice and napdice, was 96% and 74%, respectively, and the rate of absorption was not significantly different from that obtained following oral dosing of the parent compound. Stability studies in gastric and intestinal juice showed that, unlike napdice, ibudice was stable in gastric juice, with both prodrugs undergoing rapid biotransformation to their parent compounds in intestinal juice. This rapid conversion led to the lack of sustained release performance following oral administration of ibudice or napidice.


Subject(s)
Ibuprofen/pharmacokinetics , Naproxen/pharmacokinetics , Prodrugs/pharmacokinetics , Animals , Diethyl Pyrocarbonate/analogs & derivatives , Diethyl Pyrocarbonate/pharmacokinetics , Dogs , Drug Stability
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