Absorption and Mass Balance of Mgk R11 and Mgk R11 Formulated with Deet,Mgk 264, and Mgk 326 Following an 8 Hour Dermal Exposure in Human Volunteers

Abstract

Dermal absorption and excretion of MGK R11 [2,3:4,5-bis(2-butylene) tetrahydro-2 furaldehyde, McLaughlin Gormley King Company, Minneapolis, MN] was studied using [¹⁴C]MGK R11 either by itself or formulated with DEET (N,N-diethyl-m-toluamide), MGK 264 (N-octylbicycloheptene dicarboximide), and MGK 326 (di-n-propyl-isocinchomeronate). Each of these two formulations was tested on four young, healthy male volunteers, using a single topical application on the forearm under nonocclusive conditions for an 8 h period. Blood from the ipsilateral and contralateral arms, urine, and feces were collected at selected intervals during the 8 h application and through a 120 h postapplication period. The application area was also tape-stripped to determine if any of the test material accumulated in the stratum corneum. These samples provided data that permitted some insight into the kinetics of penetration and elimination processes of MGK R11. Urine samples, swabs, and skin rinse samples were analyzed by high-performance liquid chromatography (HPLC) to characterize the metabolic profile, identify the major metabolites, and determine the metabolic pathway.

MGK R11, either by itself or formulated, was poorly absorbed through the skin as shown by the amount of radioactivity excreted in the urine and the very low plasma radioactivity level in the ipsilateral plasma. When dosed by itself, approximately 8% of the dose was excreted in the urine. In contrast, only 3% of the formulated MGK R11 was excreted in the urine. Approximately 0.3% of the dose was excreted in the feces. There was no evidence of accumulation of MGK R11 in the skin, as evidenced by low amounts of radioactivity in the tape strippings. A significant portion of the dosed radioactivity was recovered from the dome covering the dosing site amounting to 67% of the compound by itself or 27% of the formulated product, indicating a difference of volatility depending on the formulation. The rest of the external radioactivity was present in the swabs. Total recovery of the applied radioactivity was 89.9% and 99.5% for MGK R11 and the formulated product, respectively. Radiochemical analyses of the swab composites indicated a 30% degradation of parent compound in the one-component swabs and no degradation in the four-component swabs. Absorbed MGK R11 was completely metabolized prior to its excretion in the urine to two metabolites that accounted for 95% of the urinary metabolites. The major metabolic pathway is by oxidation of the aldehyde to the corresponding acid or reduction of the aldehyde to the corresponding alcohol followed by conjugation to produce the glucuronide.     

Absorption, metabolism, and excretion of [14C]imidafenacin, a new compound for treatment of overactive bladder, after oral administration to healthy male subjects.

The absorption, metabolism, and excretion of imidafenacin [KRP-197/ONO-8025, 4-(2-methyl-1H-imidazol-1-yl)-2,2-diphenylbutanamide], a new antimuscarinic drug developed for treatment of overactive bladder, were assessed in six healthy male subjects after a single oral administration of 0.25 mg of [(14)C]imidafenacin (approximately 46 microCi). The highest radioactivity in the plasma was observed at 1.5 h after administration. The apparent terminal elimination half-life of the total radioactivity was 72 h. Approximately 65.6 and 29.4% of the administered radioactivity were recovered in the urine and feces, respectively, within 192 h after administration. The metabolite profiling by high-performance liquid chromatography-radiodetector and liquid chromatography/tandem mass spectrometry demonstrated that the main component of radioactivity was unchanged imidafenacin in the 2-h plasma. The N-glucuronide conjugate (M-9) was found as the major metabolite and the oxidized form of the 2-methylimidazole moiety (M-2) and the ring-cleavage form (M-4) were detected as the minor metabolites in the 2-h plasma, but M-4 was found to be the main component in the 12-h plasma. Unchanged imidafenacin, M-9, M-2, and other oxidized metabolites were excreted in the urine, but the unchanged imidafenacin and M-9 were not found in the feces. Two unique metabolites were found in the urine and feces, which were identified as the interchangeable cis- and trans-isomers of 4,5-dihydrodiol forms of the 2-methylimidazole moiety. These findings indicate that imidafenacin is rapidly and well absorbed (at least 65% of dose recovered in urine) after oral administration, circulates in human plasma as the unchanged form, its glucuronide, and other metabolites, and is then excreted in urine and feces as the oxidized metabolites of 2-methylimidazole moiety.     

Hepatobiliary elimination of bendamustin (Cytostasan) in rats.

Biliary excretion of bendamustin (Cytostasan, 5-[bis(2-chloroethyl)amino]-i-methylbenzimidazole-2-butyric acid; 1) and its metabolites was studied in rats after i.v. administration of 14C-1. The most significant finding was the rapid excretion of 1 related radioactivity in the bile occurring shortly after injection. While radioactivity eliminated by bile within 2 h was 41.8%, in the course of subsequent 22 h it amounted only to 3.2%. Bile samples analyzed by TLC indicated that the total amount of radioactivity was excreted in the form of conjugates and two hydroxy metabolites. A significant amount of radioactivity was excreted in urine. The diversion of bile by cannulation of the bile duct led to a significant decrease of elimination by feces.     

雷公藤甲素在大鼠体内过程的研究

雷公藤甲素具有抗肿瘤、抗炎和免疫抑制作用,能迅速由胃肠道吸收,但并不完全。本实验研究了该药口服和静注给药途径的分布和排泄,结果表明:口服和静注后,药物在体内的分布和消除速率大体相似,均以肝中浓度为最高,依次为脾、肺、肾、肠、心和脑,体内消除较缓慢。血浆蛋白结合率为64.7%。24d内,口服后尿粪总排泄量为给药量的67.5% ,其中粪占52.4%;静注后为61.9%,粪占25%。24h内胆汁排泄为6.73%。提取尿、粪和胆汁经TLC、放射性测定及放射自显影分析,表明以原药排泄为主和部分代谢物。     

Elimination pathways of [14C]losoxantrone in four cancer patients.

Losoxantrone is an anthrapyrazole derivative in Phase III development in the U.S. for solid tumors, notably breast cancer. To obtain information on the routes of elimination of the drug, a study was conducted in four patients with advanced solid tumors, which involved intravenous administration of 100 microCi of [14C]losoxantrone for a total dose of 50 mg/m(2) during the first course of losoxantrone therapy. Blood, urine, and feces were collected for up to 2 weeks and were analyzed for total radioactivity and parent drug. In addition, feces were profiled for the presence of metabolites. Plasma concentrations of total radioactivity exhibited a temporal pattern similar to the parent drug. Combined recovery of administered total radioactivity from urine and feces was 70% with the majority (87%) of this radioactivity excreted in the feces, presumably via biliary excretion. Feces extracts were profiled for metabolites using a high-performance liquid chromatography method developed to separate synthetic standards of previously identified human urinary metabolites. Only intact losoxantrone was found in the feces. About 9% of the dose was excreted in the urine, primarily during the first 24 h and mostly in the form of parent compound. Collectively, these data indicate that fecal excretion of unmetabolized drug via biliary and/or intestinal excretion is the primary pathway of intravenously administered losoxantrone elimination in cancer patients with refractory solid tumors.     

Disposition and metabolism of 2-(2'(1',3'-dioxolan-2-yl)-2- methyl-4-(2'-oxopyrrolidin-1-Yl)-6-nitro-2h-1-benzopyran (SKP-450) in rats.

The disposition and metabolism of the new antihypertensive agent 2-(2"(1", 3"-dioxolan-2-yl)-2-methyl-4-(2'-oxopyrrolidin-1-yl)-6-nitro -2H-1-benzopyran (SKP-450) were investigated in male rats after single oral and i.v. doses of 14C-labeled compound. After an oral 2.0 mg/kg dose, mean radiocarbon recovery was 98.2 +/- 2.3% with 31.1 +/- 7.3% in the feces and 67.1 +/- 14.3% in the urine. Biliary excretion of radioactivity for the first 24-h period was approximately 40%, suggesting that SKP-450 is cleared either by hepatobiliary excretion or by renal excretion. SKP-450 was well absorbed; bioavailability calculated on the basis of radioactivity was 68 to 97%. Tissue distribution of the radioactivity was widespread with high concentrations in the liver and kidney but low central nervous system penetration. Radio-HPLC analysis of bile and urine from rats indicated the extensive metabolism of SKP-450 into oxidative metabolites. Oxidative metabolism of the dioxolanyl ring resulted in an aldehyde intermediate, subsequently confirmed in vitro, which was further oxidized to the corresponding carboxylic acid (M1) or reduced to the corresponding alcohol (M3). No parent drug was detected in the urine or bile. Glucuronide conjugate of M3 was also detected in urine and bile, accounting for 5.8 +/- 2.1 and 8.9 +/- 3. 7% of the excreted radioactivity, respectively. Quantitative data obtained from plasma samples suggest that the majority of circulating radioactivity was associated with metabolites. Our results suggest that the long duration of pharmacological activity of SKP-450 (>10 h) is largely attributable to its metabolites.     

Metabolism and excretion of the dipeptidyl peptidase 4 inhibitor [14C]sitagliptin in humans.

The metabolism and excretion of [(14)C]sitagliptin, an orally active, potent and selective dipeptidyl peptidase 4 inhibitor, were investigated in humans after a single oral dose of 83 mg/193 muCi. Urine, feces, and plasma were collected at regular intervals for up to 7 days. The primary route of excretion of radioactivity was via the kidneys, with a mean value of 87% of the administered dose recovered in urine. Mean fecal excretion was 13% of the administered dose. Parent drug was the major radioactive component in plasma, urine, and feces, with only 16% of the dose excreted as metabolites (13% in urine and 3% in feces), indicating that sitagliptin was eliminated primarily by renal excretion. Approximately 74% of plasma AUC of total radioactivity was accounted for by parent drug. Six metabolites were detected at trace levels, each representing <1 to 7% of the radioactivity in plasma. These metabolites were the N-sulfate and N-carbamoyl glucuronic acid conjugates of parent drug, a mixture of hydroxylated derivatives, an ether glucuronide of a hydroxylated metabolite, and two metabolites formed by oxidative desaturation of the piperazine ring followed by cyclization. These metabolites were detected also in urine, at low levels. Metabolite profiles in feces were similar to those in urine and plasma, except that the glucuronides were not detected in feces. CYP3A4 was the major cytochrome P450 isozyme responsible for the limited oxidative metabolism of sitagliptin, with some minor contribution from CYP2C8.     

Isolation and identification of metabolites of 2-ethylhexyl diphenyl phosphate in rats

The metabolic fate of 2-ethylhexyl diphenyl phosphate (EHDPP) was studied in male rats. Orally administered ¹⁴C-EHDPP was rapidly absorbed and about 80% of the radioactivity was excreted in the urine and feces in the first 24 h. By 7 days, 48% and 52% of the radioactivity was recovered in urine and feces, respectively. Since biliary excretion was low (6% for 2 days), urine seems to be the major excretion route of EHDPP. Radioactivity was widely distributed in all tissues examined. At 2 h, the concentration was relatively high in blood, liver kidney and adipose tissue. The elimination of radioactivity from adipose tissue and liver was somewhat delayed, but almost all the radioactivity was eliminated by 7 days. The major metabolites in the urine were diphenyl phosphate (DPP) and phenol. p-Hydroxyphenyl phenyl phosphate (OH-DPP) and monophenyl phosphate (MPP) were also identified as minor metabolites.     

Disposition of 2-(2-quinolyl)-1,3-indandione (D. C. yellow #11) in rats dosed orally or intravenously

The disposition of 2-(2-quinolyl)-1,3-indandione (D. C. yellow #11, DCY) in male Fischer rats dosed intravenously or by feeding was determined. For rats given [14C]DCY in the feed (0.00044-0.41% of the diet), recovery of radioactivity during the 24-h dosing period and the 72-h period thereafter ranged from 89.1 to 93.9% for feces and from 4.98 to 6.25 for urine. Tissues contained only trace amounts. Following intravenous dosing with [14C]DCY (0.93 mg/kg), radioactivity distributed readily into most tissues; maximum amounts were present at 5 min, the earliest time of assay. Maximum amounts of radioactivity in fat, skin, and gut tissue, however, were present at 30 min after dosing. These three tissues also had relatively long alpha phases for the elimination of radioactivity. In 24 h after intravenous dosing, rats excreted 81.1% of the dose in the feces and 16.0% of the dose in the urine. For rats fitted with biliary cannulas, 54.5% of the dose, all of which was metabolites of [14C]DCY, was recovered in the bile in 4 h. Associated with the rapid and extensive biliary excretion of metabolites of intravenously administered [14C]DCY was the appearance of large amounts of radioactivity in the feces and also, at intermediate time points, in the liver, gut contents, and gut tissue. In conclusion, rats rapidly distribute, metabolize, and excrete [14C]DCY.     

Metabolism and excretion of piperonyl butoxide in the rat

[14C]-piperonyl butoxide (PBO) was administered to male and female rats by gavage at a dose rate of 50 or 500 mg kg-1 body weight. In all cases, the radioactivity was rapidly excreted with 87-99% being found in the 0-48-h excreta and the majority of the dose (64.1-85.0%) being eliminated in faeces. The metabolism of PBO was complex with over 25 peaks of radioactivity being seen by radio-high-performance liquid chromatography (HPLC). Using HPLC/tandem mass spectrometry (MS/MS) and nuclear magnetic resonance (NMR), 12 urine metabolites were assigned structures together with four plus PBO in faeces. Metabolism occurred at two sites: the methylenedioxy ring, which opened to form a catechol that could then undergo methylation, and the 2-(2-butoxyethoxy)ethoxymethyl side-chain, which underwent sequential oxidation to a series of alcohols and acids. The identified metabolites accounted for approximately 60% of the administered dose.     

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.     

Absorption, distribution, metabolism, and excretion of 1,2-dihydro-2,2,4-trimethylquinoline in the male F344 rat

1,2-Dihydro-2,2,4-trimethylquinoline (TMQ), an antioxidant used in the rubber industry, was readily absorbed from the gastrointestinal tract of the male Fischer 344/N rat and rapidly distributed throughout the body tissues. Absorption, distribution, metabolism, and excretion were not significantly affected by dose in the range 11.5-1150 mumol/kg. Following iv administration, the greatest amounts of TMQ-derived radioactivity were present in the high volume tissues including muscle, adipose, skin, liver, and blood. TMQ had no particular affinity for any tissue. TMQ-derived radioactivity was excreted primarily in urine (60-70%) and feces (20-30%) within 3 days after administration. Greater than 99% of the TMQ dose excreted in urine and feces was in the form of metabolites. Urine contained two major and ten minor metabolites while feces contained two major and four minor metabolites. The two major TMQ metabolites in urine were identified by NMR and mass spectroscopy as the O-sulfate conjugate of 1,2-dihydro-6-hydroxy-2,2,4-trimethylquinoline and the monosulfate conjugate of 1,2-dihydro-1,6-dihydroxy-2,2,4-trimethylquinoline. In vitro studies with liver subcellular fractions suggest that most of the metabolites present in urine, feces, and bile are the products of mixed function oxidase activity and conjugates of these metabolites. Multiple exposure of rats to high TMQ doses (1150 mumol/kg) resulted in some bioaccumulation of TMQ-derived radioactivity in all tissues examined, but these residues did not persist when dosing was discontinued.     

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.     

Mass balance study of [1?C]eribulin in patients with advanced solid tumors

This mass balance study investigated the metabolism and excretion of eribulin, a nontaxane microtubule dynamics inhibitor with a novel mechanism of action, in patients with advanced solid tumors. A single approximately 2 mg (approximately 80 μCi) dose of [1?C]eribulin acetate was administered as a 2 to 5 min bolus injection to six patients on day 1. Blood, urine, and fecal samples were collected at specified time points on days 1 to 8 or until sample radioactivity was ≤1% of the administered dose. Mean plasma eribulin exposure (627 ng · h/ml) was comparable with that of total radioactivity (568 ng Eq · h/ml). Time-matched concentration ratios of eribulin to total radioactivity approached unity in blood and plasma, indicating that unchanged parent compound constituted almost all of the eribulin-derived radioactivity. Only minor metabolites were detected in plasma samples up to 60 min postdose, pooled across patients, each metabolite representing ≤0.6% of eribulin. Elimination half-lives for eribulin (45.6 h) and total radioactivity (42.3 h) were comparable. Eribulin-derived radioactivity excreted in feces was 81.5%, and that of unchanged eribulin was 61.9%. Renal clearance (0.301 l/h) was a minor component of total eribulin clearance (3.93 l/h). Eribulin-derived radioactivity excreted in urine (8.9%) was comparable with that of unchanged eribulin (8.1%), indicating minimal excretion of metabolite(s) in urine. Total recovery of the radioactive dose was 90.4% in urine and feces. Overall, no major metabolites of eribulin were detected in plasma. Eribulin is eliminated primarily unchanged in feces, whereas urine constitutes a minor route of elimination.     

The in vivo dermal absorption and metabolism of [4-14C] coumarin by rats and by human volunteers under simulated conditions of use in fragrances.

The disposition and metabolic fate of [4-14C]coumarin in a 70% aqueous ethanol solution was studied in male Lister Hooded rats after occluded dermal application and in three male volunteers after an exposure designed to simulate that which may be encountered when using an alcohol-based perfumed product. In both cases, the 6-h exposure was 0.02 mg/cm(2) (rats 0.023 mg/kg and humans 0.77 mg/kg). In both, coumarin was quickly absorbed, distributed and excreted in urine and feces, although fecal excretion of coumarin in humans was only 1% of the applied dose as opposed to 21% in rats. Total absorption was 72% of the applied dose with rats and 60% with humans. Peak plasma radioactivity in both was at 1 h. The mean plasma half-life of coumarin and metabolites was approximately 1.7 h for humans and 5 h for rats. In humans, coumarin was primarily metabolized to and excreted in urine as 7-hydroxycoumarin glucuronide and 7-hydroxycoumarin sulfate. Small amounts of unconjugated 7-hydroxycoumarin and o-hydroxyphenylacetic acid (o-HPAA) were also excreted. In rats, about twenty metabolites were present, but only o-HPAA was identified. These studies show the rat is a very poor model for humans and toxicity in the rat cannot be extrapolated to humans.     

The disposition and metabolism of [14C]fluconazole in humans.

The disposition and metabolism of 14C-labeled fluconazole (100 microCi) was determined in three healthy male subjects after administration of a single oral capsule containing 50 mg of drug. Blood samples, total voided urine, and feces were collected at intervals after dosing for up to 12 days post-dose. Pharmacokinetic analysis of fluconazole concentrations showed a mean plasma half-life of 24.5 hr. Mean apparent plasma clearance and apparent volume of distribution were 0.23 ml/min/kg and 0.5 liter/kg, respectively. There was no evidence of any significant concentrations of metabolites circulating either in plasma or blood cells. Mean total radioactivity excreted in urine and feces represented 91.0 and 2.3%, respectively, of the administered dose. Mean excretion of unchanged drug in urine represented 80% of the administered dose; thus, only 11% was excreted in urine as metabolites. Only two metabolites were present in detectable quantities, a glucuronide conjugate of unchanged fluconazole and a fluconazole N-oxide, which accounted for 6.5 and 2.0% of urinary radioactivity, respectively. No metabolic cleavage products of fluconazole were detected.     

Biotransformation and excretion of N,N'-bis(3-(2-ethoxyphenoxy)-2-hydroxypropyl)ethylenediamine dihydrochloride (Falirytmin) in rats

Falirytmin (1) was metabolized in rats almost completely. Besides small amounts of 1 in urine and feces 18 metabolites could be separated. The proposed structures of 14 compounds demonstrate aromatic hydroxylation, N- and O-dealkylation, side-chain oxidation, alcohol dehydrogenation and N-acetylation. The main route of excretion of 1 and metabolites was with the feces. After p.o. or i.v. administration of 14C-O-ethyl-1 the average excretion of radioactivity in urine, feces and expired air was about 75% in 96 h. The residual activity in organs was about 2-2.5%. Whole-body autoradiography confirms these results. Only slight 14C-activity was seen in muscle, fat, liver, bone marrow and gut.     

Metabolism and disposition of 2,3,7,8-tetrachlorodibenzo-p-dioxin in guinea pigs

Marked interspecies variability exists in the acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), with the guinea pig being the mammalian species most sensitive to the acute toxicity of TCDD. The metabolism and disposition of TCDD was investigated in guinea pigs for 45 days following a single exposure to purified [3H]TCDD (0.56 microgram/kg, ip). Guinea pigs included in the toxicokinetic study gained body weight, maintained a normal relative body composition, and exhibited no gross signs of toxicity during the 45-day study. Approximately 36% of the dose of TCDD-derived 3H remained in the adipose tissue at 45 days following exposure to [3H]TCDD, while the liver, pelt, and skeletal muscle and carcass each contained about 7% of the administered dose. Although most of the TCDD-derived radioactivity in liver, kidney, perirenal adipose tissue, and skeletal muscle represented unchanged TCDD, from 4 to 28% of the 3H was associated with metabolites of TCDD. This unexpected finding suggests that TCDD metabolites are not efficiently excreted from guinea pigs. The urinary and fecal excretion of TCDD-derived radioactivity followed apparent first-order kinetics, with an elimination half-life of 93.7 +/- 15.5 days (mean +/- SD). HPLC analysis of urine and bile from [3H]TCDD-treated guinea pigs showed that all of the radioactivity represented metabolites of TCDD, indicating that these routes of elimination are dependent on prior metabolism of TCDD. However, 70 to 90% of the radioactivity in fecal samples was found to represent unmetabolized TCDD throughout the 45-day excretion study. The presence of TCDD in feces and its absence in bile suggest that the fecal excretion of unchanged TCDD resulted from the direct intestinal elimination of the lipophilic toxin. Furthermore, the cumulative excretion of TCDD-derived radioactivity over 45 days indicated that 74.3% of the 3H was excreted in feces as unchanged TCDD, while 25.7% of the 3H was excreted in urine and feces as TCDD metabolites. Thus, TCDD is primarily eliminated unchanged in the feces of guinea pigs, indicating that the metabolism of TCDD does not play a major role in the ultimate elimination of the toxin from the guinea pig. This may in part explain the relatively long excretion half-life for TCDD in the guinea pig and may contribute to the remarkable sensitivity of the guinea pig to the acute toxicity of TCDD.     

Metabolism and excretion of CP-122,721, a non-peptide antagonist of the neurokinin NK1 receptor, in dogs: identification of the novel cleaved product 5-trifluoromethoxy salicylic acid in plasma

The metabolism and excretion of a potent and selective substance P receptor antagonist, CP-122,721, have been studied in beagle dogs following oral administration of a single 5 mg kg(-1) dose of [(14)C]CP-122,721. Total recovery of the administered dose was on average 89% for male dogs and 95% for female dogs. Approximately 94% of the radioactivity recovered in urine and feces was excreted in the first 72 h. Male bile duct-cannulated dogs excreted a mean of approximately 56% of the dose in bile, approximately 11% in feces, and approximately 25% in urine. The sum of radioactivity in bile and urine indicates >80% of the [(14)C]CP-122,721-derived radioactivity was absorbed by the gastrointestinal tract. CP-122,721 was extensively metabolized in dogs, and only a small amount of parent CP-122,721 was excreted as unchanged drug. There were no significant gender-related quantitative/qualitative differences in the excretion of metabolites in urine or feces. The major metabolic pathways of CP-122,721 were O-demethylation, aromatic hydroxylation, and indirect glucuronidation. The minor metabolic pathways included: Aliphatic oxidation at the piperidine moiety, O-dealkylation of the trifluoromethoxy group, and N-dealkylation with subsequent sulfation and/or oxidative deamination. In addition, the novel cleaved product 5-trifluoromethoxy salicylic acid (TFMSA) was identified in plasma. These results suggest that dog is the most relevant animal species in which the metabolism of CP-122,721 can be studied for extrapolating the results to humans.     

Metabolism and excretion of CP-122,721, a non-peptide antagonist of the neurokinin NK1 receptor,in dogs: Identification of the novel cleaved product 5-trifluoromethoxy salicylic acid in plasma

The metabolism and excretion of a potent and selective substance P receptor antagonist, CP-122,721, have been studied in beagle dogs following oral administration of a single 5?mg?kg^?1 dose of [¹⁴C]CP-122,721. Total recovery of the administered dose was on average 89% for male dogs and 95% for female dogs. Approximately 94% of the radioactivity recovered in urine and feces was excreted in the first 72?h. Male bile duct-cannulated dogs excreted a mean of ～56% of the dose in bile, ～11% in feces, and ～25% in urine. The sum of radioactivity in bile and urine indicates >80% of the [¹⁴C]CP-122,721-derived radioactivity was absorbed by the gastrointestinal tract. CP-122,721 was extensively metabolized in dogs, and only a small amount of parent CP-122,721 was excreted as unchanged drug. There were no significant gender-related quantitative/qualitative differences in the excretion of metabolites in urine or feces. The major metabolic pathways of CP-122,721 were O-demethylation, aromatic hydroxylation, and indirect glucuronidation. The minor metabolic pathways included: Aliphatic oxidation at the piperidine moiety, O-dealkylation of the trifluoromethoxy group, and N-dealkylation with subsequent sulfation and/or oxidative deamination. In addition, the novel cleaved product 5-trifluoromethoxy salicylic acid (TFMSA) was identified in plasma. These results suggest that dog is the most relevant animal species in which the metabolism of CP-122,721 can be studied for extrapolating the results to humans.