Studies on the pharmacokinetics and metabolism of 4-chlorodiphenyl ether in rats

The metabolic disposition of 14C-labeled 4-chlorodiphenyl ether ([14C]4-CDE) was examined in rats following iv administration of a single dose (850 nmol/kg). [14C]4-CDE decayed rapidly from the blood since no unchanged [14C]4-CDE was detected in the blood beyond 2 hr after [14C]4-CDE administration. The dispositional kinetics of [14C]4-CDE in rats were best described by a two-compartment open pharmacokinetic model. Total radioactivity was excreted slowly from rats; about 41% and 33% of the administered dose were excreted into the urine and feces, respectively, within 1 week after chemical administration. About 5% of the total radioactivity administered to rats was excreted into the bile in 1 hr. The bulk of the radioactivity in the excreta was due to the presence of [14C]4-CDE metabolites. 14C-labeled 4'-hydroxy-4-CDE was the major metabolite and accounted for at least 90% of the radioactivity in the urine. The metabolic conversion of [14C]4-CDE to 14C-labeled 4'-hydroxy-4-CDE was corroborated by in vitro studies with liver microsomes of rats. In addition, [14C]4-CDE was converted by liver microsomes to reactive metabolites which bound irreversibly to microsomal protein. An arene oxide is suggested as the intermediate metabolite in the biotransformation of [14C]4-CDE by rats.     

Metabolic fate of premazepam, a new anti-anxiety drug, in the rat and the dog

A study of the disposition and metabolism of premazepam, 3,7-dihydro-5-phenyl-6,7-dimethyl-pyrrole[3,4-e][1,4]diazepin-2-(1 H) -one, a new anti-anxiety agent, was carried out in rats and dogs given the 14C-labeled compound iv and po. In both species, after oral administration, both total radioactivity and the unchanged drug are rapidly absorbed and peak plasma levels are reached within 0.5-1 hr in rats and 2 hr in dogs. Unchanged premazepam is cleared faster in rats than in dogs, with half-lives about 1.7 and 2.7 hr, respectively. Following oral dosage, two-thirds of the dose is eliminated in urine. From the urine of the two species, eight metabolites and unchanged premazepam were identified. N-7-Desmethyl premazepam (l) is the major metabolite in rat urine (18% of the dose) but is not present in dog urine, while 6-hydroxymethyl premazepam is the most abundant metabolite in dog urine (25% of the dose) but is absent in rat urine. Metabolites III and IV from rat and dog urine are stable derivatives of the intermediate formed by the cleavage of the imine bond of the diazepine ring. A successive hydrolysis of the amidic bond of the same intermediate originates metabolites V-VIII, which are quantitatively minor ones.     

Disposition of the novel serotonin agonist, LY228729, in monkeys and rats.

The disposition of a novel 5HT-1a agonist, LY228729, was studied in rats after oral administration and in monkeys after both i.v. and oral administration of a radiolabeled drug. Plasma concentrations of LY228729 declined with a half-life of 2.3 and 1.5 hr in monkeys after oral dosing and i.v. administration, respectively, and 1.9 hr in rats dosed orally. Peak plasma concentrations of the N-despropyl metabolite were greater than the parent drug following oral administration in both rats and monkeys and declined with a half-life of 3.2-3.5 hr. Plasma levels of total radioactivity rapidly exceeded that of the parent drug in both species. Radioactivity was eliminated more slowly, with terminal half-lives of 39.4 hr in the monkey and 48.6 hr in the rat. The parent drug and its despropyl metabolite accounted for only a small percentage of the total radioactivity in the plasma. Following i.v. and oral administration, radioactivity was eliminated predominantly in the urine of monkeys, but was distributed evenly between the urine and feces of rats. Parent drug and the N-despropyl metabolite were the major products in rat urine. In the monkey, the major metabolite was an uncharacterized polar compound.     

Metabolic disposition and irreversible binding of 1-phenylcyclohexene in rats

The metabolic disposition of l-[¹⁴C]phenylcyclohexene ([¹⁴C]PC) was examined in rats after ip or iv drug administration. Radioactivity, which was accumulated by various organs, peaked within 30 min after ip administration of [¹⁴C]PC (0.21 mg/kg). A significant amount of this radioactivity was not extractable by repeated methanol extractions, indicating irreversible binding of [¹⁴C]PC metabolite(s) to tissue proteins. Following iv administration of [¹⁴C]PC (0.42 mg/kg), [¹⁴C]PC concentrations in blood declined biphasically with time; the blood elimination half-life of [¹⁴C]PC is 77 min. About 83% of the dose given was excreted in urine and feces within 54 hr of administration. About 35% of the dose was excreted in the bile in 1 hr. At least four [¹⁴C]PC metabolites were detected in the urine or bile. The bulk of the urinary radioactivity was composed of metabolites since less than 6% of [¹⁴C]PC given was excreted unchanged in the urine.     

Absorption, distribution and excretion of 2,4-diamino-6-(2,5-dichlorophenyl)-s-triazine maleate in rats, dogs and monkeys

Absorption, distribution and excretion of 2,4-diamino-6-(2,5-dichlorophenyl)-s-triazine maleate (MN-1695) were studied in rats, dogs and monkeys after administration of [14C]-MN-1695. MN-1695 was found to be well absorbed from the small intestine after oral administration in all species examined. Plasma level of unchanged MN-1695 reached a maximum at 1 to 4 h after oral administration of [14C]-MN-1695 in rats, dogs and monkeys. The mean elimination half-life of unchanged MN-1695 from plasma was about 3, 4 and 50 h in rats, dogs and monkeys, respectively. Tissue levels of radioactivity after oral administration of [14C]-MN-1695 in rats indicated that [14C]-MN-1695 was distributed throughout the body and the radioactivity in tissues disappeared with a rate similar to that in plasma. A stomach autoradiogram after intravenous administration of [14C]-MN-1695 in the rat revealed the radioactivity localized in the gastric mucosa where MN-1695 was assumed to exert its pharmacological activity. In pregnant rats, [14C]-MN-1695 was distributed to the fetus with levels similar to maternal blood levels. After oral administration of [14C]-MN-1695 in rats, 39 to 46% of the dose was excreted into the urine and 50 to 63% of the dose into the feces, within 96 h. In dogs, about 40% of the dose was excreted into the urine and about 50% of the dose into the feces, within 6 days after oral administration. In monkeys, within 14 days after oral administration, about 60 and 30% of the dose were excreted into the urine and feces, respectively, and the main excretion route was the urine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Absorption, distribution and excretion of 3-(sulfamoyl[14C]methyl)-1,2-benziosoxazole (AD-810) in Rats, Dogs and Monkeys and of AD-810 in Men

Disposition of 3 - (sulfamoyl[14C]methyl) - 1,2-benzisoxazole ( [14C]AD-810) in rats, dogs and monkeys after oral administration in 20 mg/kg was studied. In preliminary human studies, healthy subjects ingested 200 mg of AD-810. [14C]AD-810 was found to be completely absorbed from digestive tracts in animals, since urinary and biliary excretion accounted for virtually total recovery of dosed radioactivity. Plasma levels reached maxima at several hours after administration in all species examined and decreased exponentially. In rats, tissue levels were virtually similar to plasma levels indicating rather even distribution in the body, and tissue radioactivity disappeared with the similar rate to plasma. Autoradiographic findings on the distribution were consistent with radiometric results. Radioactivity was evenly distributed in fetus in the pregnant rat with the similar level to maternal tissue levels. Like other sulfonamide derivatives, AD-810 was markedly taken up by erythrocytes in all species. [14C]AD-810 radioactivity was mostly excreted within 48 to 72 h after administration and its major route was urine in animals. In men, excretion of unchanged AD-810 and its metabolite in urine was found to be rather slow. No significant differences were found in absorption, distribution and excretion of radioactivity after 7 consecutive daily oral dosings of [14C]AD-810 in rats.     

The metabolic disposition of C-labelled carmoisine in the rat after oral and intravenous administration

The absorption, distribution and excretion of the red azo dye carmoisine (Ext. D & C No. 10) was studied in male rats. [14C]Carmoisine was administered in a dose of 200 mg/kg (25 microCi) by gavage or in the same dose (200 mg/kg; 3 microCi) by intravenous injection, and radioactivity was measured in blood, tissue, faeces and urine at different times after dosing. After oral administration of the dye, no radioactivity was detected in the brain, adipose tissue, muscle, testes, spleen or lung, and recovery of the administered activity in faeces and urine was almost complete by 32 hr. The radioactivity profile of the blood indicated rapid but poor absorption of [14C]carmoisine, a maximum radioactivity content corresponding to 0.01% of the dose per ml of blood being reached within 10 min. The decay curve for 14C radioactivity in the blood after iv injection of [14C]carmoisine indicated rapid distribution to the tissues and could be described in terms of a two-compartment mathematical model. The highest levels of radioactivity occurred in the gastro-intestinal tract and liver after the injection but after 24 hr no radioactivity was detectable in these or other tissues. All the radioactivity was recovered in the faeces and urine in the 24 hr following iv injection, the 79% of the dose present in faeces indicating active excretion of the dye and its metabolites in the bile and poor reabsorption from the intestine. The bioavailability of [14C]carmoisine, calculated from the blood-radioactivity curves after oral and iv administration, was less than 10%.     

The metabolic disposition of (S)-2-(3-tert-butylamino-2-hydroxypropoxy)-3-cyanopyridine in rats, dogs, and humans

Studies of the metabolic disposition of (S)-2-(3-tert-butylamino-2-hydroxypropoxy)-3-[14C]cyanopyridine (I) have been performed in humans, dogs, and spontaneously hypertensive rats. After an iv injection of I (5 mg/kg), a substantial fraction of the radioactivity was excreted in the feces of rats (32%) and dogs (31%). After oral administration of I (5 mg/kg) the urinary recoveries of radioactivity for rat and dog were 19% and 53%, respectively, and represented a minimum value for absorption because of biliary excretion of radioactivity. In man, bililary excretion of I appeared to be of minor significance because four male subjects, after receiving 6 mg of I p.o., excreted 76% and 9% of the dose of radioactivity in the urine and feces, respectively. Unchanged I represented 58% of the radioactivity excreted in human urine. The half-life for renal elimination of I was determined to be 4.0 +/- 0.9 /hr. In contrast, unchanged I represented 7% and 1% of excreted radioactivity in rat and dog urine, respectively. A metabolite of I common to man, dog, and rat was identified as 5-hydroxy-I, which represented approximately 5% of the excreted radioactivity in all species. Minor metabolites of I in which the pyridine nucleus had undergone additional hydroxylation were present in dog urine along with an oxyacetic acid metabolite, also bearing a hydroxylated pyridine nucleus.     

Excretion and metabolism of recainam, a new anti-arrhythmic drug, in laboratory animals and humans

The metabolic disposition of recainam, an antiarrhythmic drug, was compared in mice, rats, dogs, rhesus monkeys, and humans. Following oral administration of [14C]recainam-HCl, radioactivity was excreted predominantly in the urine of all species except the rat. Metabolite profiles were determined in excreta by HPLC comparisons with synthetic standards. In rodents and rhesus monkeys, urinary excretion of unchanged recainam accounted for 23-36% of the iv dose and 3-7% of the oral dose. Aside from quantitative differences attributable to presystemic biotransformation, metabolite profiles were qualitatively similar following oral or iv administration to rodents and rhesus monkeys. Recainam was extensively metabolized in all species except humans. In human subjects, 84% of the urinary radioactivity corresponded to parent drug. The major metabolites in mouse and rat urine and rat feces were m- and p-hydroxyrecainam. Desisopropylrecainam and dimethylphenylaminocarboxylamino propionic acid were the predominant metabolites in dog and rhesus monkey urine. Small amounts of desisopropylrecainam and p-hydroxyrecainam were excreted in human urine. Selective enzymatic hydrolysis revealed that the hydroxylated metabolites were conjugated to varying degrees among species. Conjugated metabolites were not present in rat urine or feces, while conjugates were detected in mouse, dog, and monkey urine. Structural confirmation of the dog urinary metabolites was accomplished by mass spectral analysis. The low extent of metabolism of recainam in humans suggests that there will not be wide variations between dose and plasma concentrations.     

The fate of N-nitrosodiethanolamine after oral and topical administration to rats

¹⁴C-labelled N-nitrosodiethanolamine ([¹⁴C]NDELA) was given to Osborne-Mendel rats at two dose levels, 0·5 or 50 mg/kg, by oral or topical administration. The excreta and tissues were analysed at various times from 4 hr to 1 wk after administration to determine the distribution of radioactivity. After oral administration, [¹⁴C]NDELA was rapidly absorbed from the gastro-intestinal tract, distributed throughout all organs and tissues, and then excreted, mainly via the kidneys. The tissue concentration reached a peak at 8 hr, but some activity remained after 1 wk. After topical application NDELA was slowly absorbed percutaneously, but once absorbed was distributed as in the orally dosed rats. Metabolic profiles of urine and bile samples from both the orally and topically dosed rats were identical, although the quantities varied. In addition to unchanged NDELA, one metabolite was present. The dose level had little effect on the quantities of unchanged NDELA or the metabolite present.     

Metabolic disposition of trimetrexate, a nonclassical dihydrofolate reductase inhibitor, in rat and dog

The metabolic disposition of trimetrexate, a nonclassical inhibitor of dihydrofolate reductase, was characterized in the rat. After iv administration of 1.2 mg/kg [14C]trimetrexate (as the glucuronate), recovery of total radioactivity in urine and feces through 144 hr was greater than 96% of dose. Trimetrexate was extensively metabolized, with only 13% of the dose excreted unchanged in urine and bile. Profiling of biliary and urinary radioactivity showed three components and unchanged drug accounted for the majority of excreted radioactivity (75% of dose). Tandem mass spectral analysis of one urinary component suggested trimetrexate had undergone N-dealkylation and oxidation to 2,4-diamino-5-methyl-6-quinazolinecarboxylic acid. Structural assignment for this metabolite was confirmed by comparison to authentic reference material. Mass spectral analysis of a second component gave a quasimolecular ion (MH)+ at m/z 532 with a key fragment ion at m/z 356 (MH-176)+, characteristic of a glucuronide conjugate. The proton NMR spectrum of this component was consistent with expectations for a glucuronide conjugate of 4'-O-desmethyl trimetrexate. Possible formation of a sulfate conjugate was explored by co-administration of unlabeled trimetrexate with [35S]sulfate to rats. A 35S-labeled component was excreted in urine, which co-eluted with the third major urinary 14C-labeled component observed in the first experiment. Mass spectrum of this component was consistent with the structure of trimetrexate-4'-O-desmethyl sulfate. In dogs, the disposition of trimetrexate was examined using stable isotope-labeled material. The dose was 10 mg/kg administered iv as a 1:1 mixture of 13C2, 15N-labeled and unlabeled trimetrexate glucuronate.(ABSTRACT TRUNCATED AT 250 WORDS)     

The disposition and pharmacokinetics of alpidem, a new anxiolytic, in the rat.

The autoradiographic distribution, disposition, biliary excretion, and pharmacokinetics of alpidem in Sprague-Dawley rats were evaluated after iv or oral administration. Following i.v. administration, autoradiography showed that radioactivity was preferentially localized in lipid-rich tissues including central nervous system structures. After a 3-mg.kg-1 i.v. or oral dose of [14C]alpidem, more than 80% of the radioactivity were excreted in the feces over a 6-day period. Biliary excretion of radioactivity in vigile rats, about 74% of the dose over a 7-hr period after either iv or oral administration, showed that alpidem was well absorbed. The absolute bioavailability (13%) data indicated a high first-pass effect. Plasma pharmacokinetic parameters of alpidem were as follows: Vd = 5 liter.kg-1, Cl = 2.2 liter.h-1.kg-1, and terminal t 1/2 beta = 1.2-1.7 hr. Three metabolites with a pharmacological activity similar to that of alpidem were detected in plasma. They were eliminated from the central compartment with half-lives comparable to that of the parent drug. Alpidem crossed the blood-brain barrier following either i.v. or oral administration, resulting in cerebral levels 2.5 to 4 times greater than the plasma levels. Alpidem was eliminated from the central nervous system according a biphasic process with a t 1/2 alpha comparable in plasma and brain. Alpidem represented 94 and 63% of cerebral radioactivity 5 min after i.v. and oral administration, respectively. Two out of the three active plasma metabolites were detected in the brain.     

Tissue distribution, disposition, and metabolism of cyclosporine in rats

Tissue distribution, disposition, and metabolism of 3H-cyclosporine were studied in rats after single and repeated oral doses of 10 and 30 mg/kg and after an iv dose of 3 mg/kg. The oral doses of 10 and 30 mg/kg were dissolved in polyethylene glycol 200/ethanol or in olive oil/Labrafil/ethanol. Absorption from both formulations was slow and incomplete, with peak 3H blood levels at 3-4 hr. Approximately 30% of the radioactive dose was absorbed, which is consistent with oral bioavailability data for cyclosporine. More than 70% of the radioactivity was excreted in feces and up to 15% in urine. Elimination via the bile accounted for 10 and 60% of the oral and iv doses, respectively. Since unchanged cyclosporine predominated in both blood and tissues at early time points, the half-lives of the distribution phases (t 1/2 alpha) of parent drug and of total radioactivity were similar. In blood, kidney, liver, and lymph nodes, t 1/2 alpha of cyclosporine ranged from 6-10 hr. Elimination of radioactivity from the systemic circulation was multiphasic, with a terminal half-life of 20-30 hr. 3H-Cyclosporine was extensively distributed throughout the body, with highest concentrations in liver, kidney, endocrine glands, and adipose tissue. The concentrations of both total radioactivity and parent drug were greater in tissues than in blood, which is consistent with the high lipid solubility of cyclosporine and some of its metabolites. Skin and adipose tissue were the main storage sites for unchanged cyclosporine. Elimination half-lives were slower for most tissues than for blood and increased with multiple dosing. The amount of unchanged drug was negligible in urine and bile.(ABSTRACT TRUNCATED AT 250 WORDS)     

The metabolism of etintidine in rat, dog, and human

The metabolic fate of etintidine, a new H2-receptor antagonist, was studied in the rat, dog, and human. Following oral or iv administration of [14C]etintidine HCl to rats, 63-72% of the dose was eliminated in urine and 15-28% in feces over 3 days. In dogs, 52-70% of the administered dose was excreted in urine and 14-18% in feces over 5 days. In the urine of both species, the major portion (generally greater than 70%) of the radioactivity was associated with parent drug and its sulfoxide metabolite. In rats, a distinct sex-related difference in metabolism was observed following oral administration of 20 mg/kg doses, with males excreting nearly twice the amount of the sulfoxide relative to females. A significant sex-related difference in metabolism was not observed in dogs following oral administration of a comparable dose, nor was it observed in either species following iv drug administration. After oral administration of [14C]etintidine HCl to human volunteers, about 86% of the dose was recovered in urine and 13% in the feces over a 7-day period. In humans, the major urinary metabolite was the N'-glucuronide conjugate. Thus, sulfoxidation does not appear to be the major urinary metabolic pathway of the drug in humans, as it is in animals. The metabolic fate of etintidine and cimetidine, another H2-receptor antagonist, are compared in three species.     

2-Chloroacetaldehyde, a metabolite of cyclophosphamide in the rat

Following simultaneous i.v. administration of a mixture of [4-14C]cyclophosphamide (14C-CP) and [side-chain 3H]CP to rats, a metabolite containing predominantly 3H radioactivity was excreted in the urine. The 3H-labelled urinary metabolite was identified as 2-chloroacetaldehyde. Chloro[3H]acetaldehyde accounted for approx. 3.8% of urinary 3H radioactivity. The importance of chloroacetaldehyde as a toxic metabolite of CP is discussed, particularly in relation to haemorrhagic bladder disease.     

Disposition and metabolism of letosteine in rats

The metabolism and disposition of letosteine, labeled either with 14C or 35S, has been investigated in Sprague-Dawley rats. In separate experiments, rats received 20 mg/kg, iv or orally, [14C]letosteine or [35S]letosteine. Radioactivity was rapidly excreted, mainly in urine, after iv and oral administration. Recovery of radioactivity from 0-72-hr excreta averaged 95% after both routes of [14C]letosteine administration, whereas only 50% was recovered when [35S]letosteine was administered. 14CO2 accounted for about 7.3% (iv) and 5.1% (po) of the dose of [14C]letosteine. Comparison of the iv and oral areas under the plasma 14C radioactivity concentration-time curves suggested that oral absorption of letosteine was complete. Analysis of the radioactivity content of urine showed that letosteine undergoes rapid and extensive metabolism. Several metabolites were identified by TLC, HPLC, and MS. The findings are consistent with a splitting of the ester group of letosteine and subsequent cleavage of the thiazolidinyl ring, yielding cysteine, hypotaurine, taurine, and inorganic sulfate. The metabolite derived from the side chain was identified in the urine as 3-(hydroxycarbonylmethylthio)propanoic acid. It undergoes further oxidation into sulfoxide and sulfone derivatives, which are also present in the urine.     

Metabolism and disposition of the flame retardant plasticizer, tri-p-cresyl phosphate, in the rat

The metabolism and disposition of tri-p-cresyl phosphate (TPCP) were studied in the rat after a single oral administration of [methyl-14C] TPCP. At a dosage of 7.8 mg/kg, most of the administered radioactivity was excreted in the urine (41%) and feces (44%) in 7 days. For 3 days, the expiratory excretion as 14CO2 amounted to 18% of the radioactivity, but was reduced to 3% by treatment of the animal with neomycin. In separate rats, the biliary excretion amounted to 28% of the dose in 24 hr. At a dose of 89.6 mg/kg, the radioactivity was excreted in urine (12%) and feces (77%) in 7 days, and the expired air (6%) in 3 days. At 24, 72, and 168 hr after oral administration, the concentration of radioactivity was relatively high in adipose tissue, liver, and kidney. The major urinary metabolites were p-hydroxybenzoic acid, di-p-cresyl phosphate (DCP), and p-cresyl p-carboxyphenyl phosphate (1coDCP). The biliary metabolites were DCP, 1coDCP, and the oxidized triesters, di-p-cresyl p-carboxyphenyl phosphate (1coTPCP), and p-cresyl di-p-carboxyphenyl phosphate (2coTPCP). The main fecal metabolite was TPCP, and the others were similar to those of bile. Following oral administration, TPCP was absorbed from the intestine, distributed to the fatty tissues, and moderately metabolized to a variety of products of oxidation and dearylation of TPCP, which were then excreted in the urine, feces, bile, and expired air. The intestinal microflora appeared to play an important role in degrading biliary metabolites to 14CO2 through the enterohepatic circulation in rats.     

Studies on the metabolism of deoxynivalenol in the rat

The metabolism and tissue distribution of [14C]deoxynivalenol have been studied in male PVG rats. Following administration of a single oral 10-mg/kg dose, radioactivity excreted in the urine and faeces accounted, respectively, for 25 and 64% of the administered dose within 96 hr. Less than 0.15% of the dose was detected in the respired air. Very little radioactivity appeared to be retained in any of the tissues examined after 96 hr. HPLC separation of several urinary and faecal metabolites was achieved on a reversed-phase column, using two different elution systems, one at neutral pH and one acidified. Two of the major non-polar HPLC peaks were identified by gas chromatography-mass spectrometry as unchanged deoxynivalenol and 3 alpha,7 alpha,15-trihydroxytrichothec-9,12-dien-8-one.     

Studies on the metabolism of meptazinol,a new analgesic drug.

1 The absorption, metabolism and excretion of the new analgesic meptazinol has been studied in male volunteers following oral and intravenous administration of a mixture of the [1-14C] and [7-3H] labelled compound. 2 After oral dosage, absorption from the gastrointestinal tract was rapid as evidenced by the early attainment of peak plasma radioactivity levels and near complete as shown by only small amounts of radioactivity recovered in the faeces. 3 Although the absorption of the drug was good, the systemic bioavailability was relatively low. Plasma levels of the unchanged drug remained below the limit of detection (20 ng/ml) after an oral dose of 200 mg. However, after intravenous administration of only 20 mg the peak plasma level was approximately 58 ng/ml. Subsequent elimination was rapid and proceeded in an apparently mono exponential manner with a half-life of approximately 2 hours. 4 Excretion of radioactivity was rapid irrespective of the dosage route and took place chiefly via the urine. Over 60% of the administered radioactivity was recovered in the 0-24 h urine collection. Less than 10% of the administered dose was excreted in the faeces. 5 Less than 5% of the drugs was excreted unchanged. The major metabolite appeared to be the glucuronide conjugate of the parent drug. No evidence was found for N-demethylation of the compound. A minor metabolite of the drug which accounted for approximately 7% of the recovered radioactivity has been tentatively identified as 6-ethyl - 6 - (3-hydroxyphenyl) - 1 - methyl-hexahydroazepin - (2H)-2-ONE.     

Pharmacokinetics, tissue distribution, metabolism, and excretion of celecoxib in rats.

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.