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1.
Xenobiotica ; 30(7): 731-44, 2000 Jul.
Article in English | MEDLINE | ID: mdl-10963063

ABSTRACT

1. The metabolism and excretion of celecoxib, a specific cyclooxygenase 2 (COX-2) inhibitor, was investigated in mouse, rabbit, the EM (extensive) and PM (poor metabolizer) dog, and rhesus and cynomolgus monkey. 2. Some sex and species differences were evident in the disposition of celecoxib. After intravenous (i.v.) administration of [14C]celecoxib, the major route of excretion of radioactivity in all species studied was via the faeces: EM dog (80.0%), PM dog (83.4%), cynomolgus monkey (63.5%), rhesus monkey (83.1%). After oral administration, faeces were the primary route of excretion in rabbit (72.2%) and the male mouse (71.1%), with the remainder of the dose excreted in the urine. After oral administration of [14C]celecoxib to the female mouse, radioactivity was eliminated equally in urine (45.7%) and faeces (46.7%). 3. Biotransformation of celecoxib occurs primarily by oxidation of the aromatic methyl group to form a hydroxymethyl metabolite, which is further oxidized to the carboxylic acid analogue. 4. An additional phase I metabolite (phenyl ring hydroxylation) and a glucuronide conjugate of the carboxylic acid metabolite was produced by rabbit. 5. The major excretion product in urine and faeces of mouse, rabbit, dog and monkey was the carboxylic acid metabolite of celecoxib.


Subject(s)
Cyclooxygenase Inhibitors/pharmacokinetics , Sulfonamides/pharmacokinetics , Animals , Celecoxib , Chromatography, High Pressure Liquid , Dogs , Feces/chemistry , Female , Macaca fascicularis , Macaca mulatta , Male , Mass Spectrometry , Mice , Pyrazoles , Rabbits , Species Specificity
2.
Drug Metab Dispos ; 28(5): 514-21, 2000 May.
Article in English | MEDLINE | ID: mdl-10772629

ABSTRACT

The pharmacokinetics, tissue distribution, metabolism, and excretion of celecoxib, 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide, a cyclooxygenase-2 inhibitor, were investigated in rats. Celecoxib was metabolized extensively after i.v. administration of [(14)C]celecoxib, and elimination of unchanged compound was minor (less than 2%) in male and female rats. The only metabolism of celecoxib observed in rats was via a single oxidative pathway. The methyl group of celecoxib is first oxidized to a hydroxymethyl metabolite, followed by additional oxidation of the hydroxymethyl group to a carboxylic acid metabolite. Glucuronide conjugates of both the hydroxymethyl and carboxylic acid metabolites are formed. Total mean percent recovery of the radioactive dose was about 100% for both the male rat (9.6% in urine; 91.7% in feces) and the female rat (10.6% in urine; 91.3% in feces). After oral administration of [(14)C]celecoxib at doses of 20, 80, and 400 mg/kg, the majority of the radioactivity was excreted in the feces (88-94%) with the remainder of the dose excreted in the urine (7-10%). Both unchanged drug and the carboxylic acid metabolite of celecoxib were the major radioactive components excreted with the amount of celecoxib excreted in the feces increasing with dose. When administered orally, celecoxib was well distributed to the tissues examined with the highest concentrations of radioactivity found in the gastrointestinal tract. Maximal concentration of radioactivity was reached in most all tissues between 1 and 3 h postdose with the half-life paralleling that of plasma, with the exception of the gastrointestinal tract tissues.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Sulfonamides/pharmacokinetics , Animals , Area Under Curve , Bile/metabolism , Bile Ducts/physiology , Biotransformation , Celecoxib , Chromatography, High Pressure Liquid , Feces/chemistry , Female , Half-Life , Injections, Intravenous , Male , Pyrazoles , Rats , Rats, Sprague-Dawley , Sulfonamides/administration & dosage , Tissue Distribution
3.
Brain Res ; 602(1): 138-42, 1993 Jan 29.
Article in English | MEDLINE | ID: mdl-8383568

ABSTRACT

The binding of radiolabeled naltrindole ([3H]NTI), a selective delta-opioid antagonist, was characterized using receptor autoradiography. Receptor binding properties were established in brain paste slices which demonstrated one site receptor occupancy with an apparent Kd of 0.25 +/- 0.08 nM (Bmax of 597.5 fmol/mg protein). Autoradiographic localization of [3H]NTI binding sites in the rat brain revealed high densities of these sites in the cortex (layers 1-3 and 6), caudate putamen, accumbens, claustrum, and internal plexiform layer of the olfactory bulb. Moderate to low levels of specific binding were observed in the hippocampus, thalamus, and substantia gelatinosa of the spinal cord.


Subject(s)
Brain Chemistry/physiology , Indoles/metabolism , Morphinans/metabolism , Naltrexone/analogs & derivatives , Receptors, Opioid, delta/metabolism , Animals , Autoradiography , Binding Sites/physiology , In Vitro Techniques , Male , Microscopy , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, Opioid, delta/antagonists & inhibitors , Tritium
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