Excretion and biotransformation of cisapride in rats after oral administration

The excretion and biotransformation of cisapride, a novel gastrokinetic drug, were studied after single (10, 40, and 160 mg/kg) and repeated (10 mg/kg/day) po administration to rats, using three different radiolabels. In fasted rats, cisapride was absorbed almost completely, except for the 160 mg/kg dose. Cisapride was metabolized extensively to at least 30 metabolites. The excretion of the metabolites amounted to more than 80% of the dose at 24 hr and was almost complete at 96 hr after dosing. In bile duct-cannulated rats, 60% was excreted in the bile within 24 hr, 45% of which underwent enterohepatic circulation. The main urinary metabolites, 4-fluorophenyl sulfate and norcisapride, primarily resulted from the N-dealkylation at the piperidine. Another major metabolic pathway was aromatic hydroxylation, occurring on either the 4-fluorophenoxy or the benzamide rings. The resulting phenolic metabolites were eliminated as conjugates in the bile; a large portion of them were subjected to a rapid enterohepatic circulation before their final excretion in the feces. Minor metabolic pathways included piperidine oxidation, O-dealkylation, O-demethylation of the methoxy substituent at the benzamide, and amine glucuronidation. Only minor quantitative dose- and sex-dependent differences could be observed for the mass balance of the metabolites. Upon repeated po dosing, steady state excretion rates were already attained after two to three doses, and excretion and metabolite patterns were very similar to those after single dose administration.     

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.     

Excretion and biotransformation of alfentanil and sufentanil in rats and dogs

The excretion and biotransformation of alfentanil (ALF) and sufentanil (SUF), two recent analogues of the synthetic opioid fentanyl, were studied after single iv administration of the tritium-labeled drugs in male rats and dogs. The drugs were almost completely metabolized in the two species, which resulted in a large number of metabolites. The excretion of the metabolites was rapid and exceeded 95% within 4 days, except for that of ALF metabolites in dogs (about 85%). For ALF, excretion of the radioactivity with the urine (73% in rats, about 76% in dogs) exceeded that with the feces. For SUF, excretion of the radioactivity with the urine amounted to 38 and 60% and that with the feces to 62 and 40%, in rats and dogs, respectively. Bile-cannulated rats excreted 68% with the bile within 24 hr after SUF dosing, and about 22% of this biliary radioactivity was subjected to enterohepatic circulation. After an ALF dose, the biliary excretion amounted to 24%, and the enterohepatic circulation was minimal. The main metabolic pathways of the two drugs were the oxidative N-dealkylation at the piperidine nitrogen and at the amide nitrogen, oxidative O-demethylation, aromatic hydroxylation, and the formation of ether glucuronides. N-[4-(Hydroxymethyl)-4-piperidinyl]-N-phenylpropanamide (M6) was the main metabolite of both ALF and SUF in rats. In dogs, the glucuronide of N-(4-hydroxyphenyl)propanamide (M5) was the main metabolite of ALF. After SUF dosing in dogs, N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide was more abundant than M5.     

Evaluation of the absorption, excretion, and metabolism of the antihypertensive agent RWJ-26899 in male and female CR Wistar rats and Beagle dogs.

The absorption, excretion and metabolism of N-(2, 6-dichlorophenyl)-beta-[[(1-methylcyclohexyl)methoxylmethyl]-N-(phenylmethyl)-1-pyrrolidineethanamine (RWJ-26899; McN-6497) has been investigated in male and female CR Wistar rats and beagle dogs. Radiolabeled [14C] RWJ-26899 was administered to rats as a single 24 mg/kg suspension dose while the dogs received 15 mg/kg capsules. Plasma (0-36 h; rat and 0-48 h; dog), urine (0-192 h; rat and dog) and fecal (0-192 h; rat and dog) samples were collected and analyzed. There were no significant gender differences observed in the data. The terminal half-life of the total radioactivity for rats from plasma was estimated to be 7.7 +/- 0.6 h while for dogs it was 22.9 +/- 4.4 h. Recoveries of total radioactivity in urine and feces for rats were 8.7 +/- 2.9% and 88.3 +/- 10.4% of the dose, respectively. Recoveries of total radioactivity in urine and feces for dogs were 4.1 +/- 1.4% and 90.0 +/- 4.7% of the dose, respectively. RWJ-26899 and a total of nine metabolites were isolated and tentatively identified in rat urine, and fecal extracts. Unchanged RWJ-26899 accounted for approximately 1% of the dose in rat urine and 8% in rat feces. RWJ-26899 and a total of four metabolites were isolated and identified in dog urine, and fecal extracts. Unchanged RWJ-26899 accounted for approximately 1% of the dose in urine and 63% in feces in dog. Five proposed pathways were used to describe the metabolites found in rats: N-oxidation, oxidative N-debenzylation, pyrrolidinyl ring hydroxylation, phenyl hydroxylation and methyl or cyclohexyl hydroxylation. Two biotransformation pathways in dogs are proposed: N-oxidation and methyl or cyclohexyl ring hydroxylation.     

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.     

Metabolism and excretion of RWJ-333369 [1,2-ethanediol, 1-(2-chlorophenyl)-, 2-carbamate, (S)-] in mice, rats, rabbits, and dogs.

The in vivo metabolism and excretion of RWJ-333369 [1,2-ethanediol, 1-(2-chlorophenyl)-, 2-carbamate, (S)-], a novel neuromodulator, were investigated in mice, rats, rabbits, and dogs after oral administration of (14)C-RWJ-333369. Plasma, urine, and feces samples were collected, assayed for radioactivity, and profiled for metabolites. In almost all species, the administered radioactive dose was predominantly excreted in urine (>85%) with less than 10% in feces. Excretion of radioactivity was rapid and nearly complete at 96 h after dosing in all species. Unchanged drug excreted in urine was minimal (<2.3% of the administered dose) in all species. The primary metabolic pathways were O-glucuronidation (rabbit > mouse > dog > rat) of RWJ-333369 and hydrolysis of the carbamate ester followed by oxidation to 2-chloromandelic acid. The latter metabolite was subsequently metabolized in parallel to 2-chlorophenylglycine and 2-chlorobenzoic acid (combined hydrolytic and oxidative pathways: rat > dog > mouse > rabbit). Other metabolic pathways present in all species included chiral inversion in combination with O-glucuronidation and sulfate conjugation (directly and/or following hydroxylation of RWJ-333369). Species-specific pathways, including N-acetylation of 2-chlorophenylglycine (mice, rats, and dogs) and arene oxidation followed by glutathione conjugation of RWJ-333369 (mice and rats), were more predominant in rodents than in other species. Consistent with human metabolism, multiple metabolic pathways and renal excretion were mainly involved in the elimination of RWJ-333369 and its metabolites in animal species. Unchanged drug was the major plasma circulating drug-related substance in the preclinical species and humans.     

Absorption, metabolism and excretion of ketanserin in man after oral administration

The absorption, metabolism and excretion of ketanserin [+)-3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,4(1H,3H)- quinazolinedione, R 41 468), a novel serotonin S2-receptor antagonist used in hypertension, was studied after a single oral dose of 14C-ketanserin tartrate in three healthy subjects. Absorption from the gastrointestinal tract was rapid and almost complete. The excretion of radioactivity amounted to about 90% after 4 days and was more abundant in urine (68%) than in faeces (24%). Ketone reduction and oxidative N-dealkylation at the piperidine nitrogen were by far the two main metabolic pathways. The former pathway resulted in ketanserin-ol, the main metabolite in plasma as well as in urine (24% of dose) and faeces (5%), the latter pathway in the urinary metabolite 1,4-dihydro-2,4-dioxo-3(2H)quinazolineacetic acid (20%). Other pathways were aromatic hydroxylation at the quinazolinedione moiety and the formation of ether glucuronides. None of the metabolites substantially contributes to the overall pharmacological activity of ketanserin. The metabolic pathways of ketanserin in man were identical to those revealed previously in rats and dogs, but the mass balance of the major metabolites resembled more that in dogs than that in rats.     

The metabolism and excretion of galantamine in rats, dogs, and humans.

Galantamine is a competitive acetylcholine esterase inhibitor with a beneficial therapeutic effect in patients with Alzheimer's disease. The metabolism and excretion of orally administered (3)H-labeled galantamine was investigated in rats and dogs at a dose of 2.5 mg base-Eq/kg body weight and in humans at a dose of 4 mg base-Eq. Both poor and extensive metabolizers of CYP2D6 were included in the human study. Urine, feces, and plasma samples were collected for up to 96 h (rats) or 168 h (dogs and humans) after dosing. The radioactivity of the samples and the concentrations of galantamine and its major metabolites were analyzed. In all species, galantamine and its metabolites were predominantly excreted in the urine (from 60% in male rats to 93% in humans). Excretion of radioactivity was rapid and nearly complete at 96 h after dosing in all species. Major metabolic pathways were glucuronidation, O-demethylation, N-demethylation, N-oxidation, and epimerization. All metabolic pathways observed in humans occurred in at least one animal species. In extensive metabolizers for CYP2D6, urinary metabolites resulting from O-demethylation represented 33.2% of the dose compared with 5.2% in poor metabolizers, which showed correspondingly higher urinary excretion of unchanged galantamine and its N-oxide. The glucuronide of O-desmethyl-galantamine represented up to 19% of the plasma radioactivity in extensive metabolizers but could not be detected in poor metabolizers. Nonvolatile radioactivity and unchanged galantamine plasma kinetics were similar for poor and extensive metabolizers. Genetic polymorphism in the expression of CYP2D6 is not expected to affect the pharmacodynamics of galantamine.     

Nitrilotriacetate (NTA): human metabolism and its importance in the total safety evaluation program

Ten milligrams [¹⁴C]NTA in gelatin capsules was given (po) to 8 male subjects. Blood samples were taken, and samples of urine and feces were collected. In addition, expired CO₂ was collected in 4 of the subjects. NTA is poorly absorbed since approximately 12% of the dose appeared in the urine. The compound is rapidly excreted in the urine since 87% of the absorbed dose was excreted within the first 24 hr post dosing. The blood concentration peak occurred 1–2 hr after dosing. Reverse isotope dilution and thin-layer chromatography showed the urinary radioactivity to be unchanged NTA, and therefore no biotransformation had occurred. These results closely resemble the rat and dog metabolic data except that rats and dogs absorb 4 times more NTA than humans. The metabolic similarities among rats, dogs and humans lends some confidence to the extrapolation of the results derived from rat and dog toxicity tests for the purpose of estimating human safety.     

Metabolism and pharmacokinetics of 4-(p-chlorophenylthio)butanol (W-2719) in the rat and dog

4-(p-Chlorophenylthio)butanol (W-2719) administered orally to rats and dogs is rapidly absorbed, metabolized and excreted. The only major biotransformation product found in blood was p-chlorophenylthioacetic acid (W-2683). No W-2719 or the intermediary p-chlorophenylthiobutyric acid (W-2718) could be found in plasma after oral administration of the drug. When W-2719 was given i.v. to dogs, both W-2719 and W-2718 appeared in plasma but each had a very short half-life of about 10 min. After an oral dose of W-2719 to dogs the plasma content of W-2683 peaked at 4-6 h, amounting to approximately 20% of the dose. More than 91% of the dose was excreted with 48 h, 83% in urine and 9% in feces. The predominant excretion product in urine was p-chlorothiophenol, most of which was excreted in a conjugated form. The other major urinary metabolite was W-2683, while smaller amounts of W-2718 and unchanged drug were also found. No significant effect of prolonged dosing of 14C-W-2719 to dogs was observed on plasma 14C levels, peak time, 14C half-life or excretion and composition patterns.     

Metabolism and excretion of erlotinib, a small molecule inhibitor of epidermal growth factor receptor tyrosine kinase, in healthy male volunteers.

Metabolism and excretion of erlotinib, an orally active inhibitor of epidermal growth factor receptor tyrosine kinase, were studied in healthy male volunteers after a single oral dose of [14C]erlotinib hydrochloride (100-mg free base equivalent, approximately 91 microCi/subject). The mass balance was achieved with approximately 91% of the administered dose recovered in urine and feces. The majority of the total administered radioactivity was excreted in feces (83+/-6.8%), and only a low percentage of the dose was recovered in urine (8.1+/-2.8%). Only less than 2% of what was recovered in humans was unchanged erlotinib, which demonstrates that erlotinib is eliminated predominantly by metabolism. In plasma, unchanged erlotinib represented the major circulating component, with the pharmacologically active metabolite M14 accounting for approximately 5% of the total circulating radioactivity. Three major biotransformation pathways of erlotinib are O-demethylation of the side chains followed by oxidation to a carboxylic acid, M11 (29.4% of dose); oxidation of the acetylene moiety to a carboxylic acid, M6 (21.0%); and hydroxylation of the aromatic ring to M16 (9.6%). In addition, O-demethylation of M6 to M2, O-demethylation of the side chains to M13 and M14, and conjugation of the oxidative metabolites with glucuronic acid (M3, M8, and M18) and sulfuric acid (M9) play a minor role in the metabolism of erlotinib. The identified metabolites accounted for >90% of the total radioactivity recovered in urine and feces. The metabolites observed in humans were similar to those found in the toxicity species, rats and dogs.     

Evaluation of the excretion, and metabolism of the cardiotonic agent bemoradan in male rats and female beagle dogs.

The excretion and metabolism of (+/-) [6-(3,4-dihydro-3-oxo-1,4[2H]-benzoxazine-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one] (bemoradan; RWJ-22867) have been investigated in male Long-Evans rats and female beagle dogs. Radiolabeled [14C] bemoradan was administered to rats as a singkle 1 mg/kg suspension dose while the dogs received 0.1 mg/kg suspension dose. Plasma (0-24 h; rat and dog), urine (0-72 h; rat and dog) and fecal (0-72 h; rat and dog) samples were collected and analyzed. The terminal half-life of the total radioactivity for rats from plasma was estimate to be 4.3 +/- 0.1 h while for dogs it was 7.5 +/- 1.3 h. Recoveries of total radioactivity in urine and feces for rats were 49.1 +/- 2.4% and 51.1 +/- 4.9% of th dose, respectively. Recoveries of total radioactivity in urine and feces for dogs were 56.2 +/- 12.0% and 42.7 V 9.9% of the dose, respectively. Bemoradan and a total of nine metabolites were isolated and tentatively identified in rat and dog plasma, urine, and fecal extracts. Unchanged bemoradan accounted for approimately < 2% of the dose in rat urine and 20% in rat feces. Unchanged bemoradan accounted for approximately 5% of the dose in urine and 16% in feces in dog. Six proposed pathways were used to describe the metabolites found in rats and dogs: pyridazinyl oxidations, methyl hydroxylation, hydration, N-oxidation, dehydration and phase II conjugations.     

Disposition and pharmacokinetics of [14C]finasteride after oral administration in humans.

The disposition of [14C]finasteride, a competitive inhibitor of steroid 5 alpha-reductase, was investigated after oral administration of 38.1 mg (18.4 microCi) of drug in six healthy volunteers. Plasma, urine, and feces were collected for 7 days and assayed for total radioactivity. Concentrations of finasteride and its neutral metabolite, omega-hydroxyfinasteride (monohydroxylated on the t-butyl side chain), in plasma and urine were determined by HPLC assay. Mean excretion of radioactivity equivalents in urine and feces equaled 39.1 +/- 4.7% and 56.8 +/- 5.0% of the dose, respectively. The mean peak plasma concentrations reached for total radioactivity (ng equivalents), finasteride, and omega-hydroxyfinasteride were 596.5 +/- 88.3, 313.8 +/- 99.4, and 73.7 +/- 11.8 ng/ml, respectively, at approximately 2 hr; the mean terminal half-life for drug and metabolite was 5.9 +/- 1.3 and 8.4 +/- 1.7 hr, respectively. Of the 24-hr plasma radioactivity, 40.9% was finasteride, 11.8% was the neutral metabolite, and 26.7% was characterized as an acidic fraction of radioactivity. Binding of [14C]finasteride to plasma protein was extensive (91.3 to 89.8%), with a trend suggesting concentration dependency (range 0.02 to 2 micrograms/ml). Little of the dose was excreted in urine as parent (0.04%) or omega-hydroxyfinasteride (0.4%). Urinary excretion of radioactivity was largely in the form of acidic metabolite(s)--18.4 +/- 1.7% of the dose was eliminated as the omega-monocarboxylic acid metabolite. Finasteride was scarcely excreted unchanged in feces. In humans, finasteride is extensively metabolized through oxidative pathways.(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.     

Metabolism of retigabine (D-23129), a novel anticonvulsant.

Retigabine (D-23129, N-(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid ethyl ester) is a potent anticonvulsant in a variety of animal models. Rats metabolized [14C]retigabine mainly through glucuronidation and acetylation reactions. Glucuronides were detected in incubates with liver microsomes or slices, in plasma, and in bile and feces but were absent in urine (0-24 h) that contained about 2% of the dose as retigabine and approximately 29% of the dose in > 20 metabolites, which are derived mainly from acetylation reactions. About 67% of the radioactivity was excreted into feces, approximately 10% of the dose as glucuronide. The metabolite pattern in the urine (0-24 h) of dogs was comparatively simple in that retigabine (13%), retigabine-N-glucuronide (5%), and retigabine-N-glucoside (1%) were present. In the same 24-h interval, about 39% of unchanged retigabine was excreted into feces. Plasma profiling and spectroscopic analysis (liquid chromatography with tandem mass spectrometry NMR) of two isolated urinary metabolites obtained after single oral dosing of 600 mg retigabine in healthy volunteers indicated that both acetylation and glucuronidation are major metabolic pathways of retigabine in humans. We found that in vitro assays with liver slices from rat and humans reveal the major circulating metabolites in vivo.     

The metabolism of 14C-cibenzoline in dogs and rats

The disposition of the new antiarrhythmic agent cibenzoline (CBZ) (racemic 4,5-dihydro-2-(2,2-diphenylcyclopropyl)-1H-imidazole) in three male dogs was investigated after oral administration of 13.8 mg/kg of 14C-CBZ base. Within 6 days, 60.5 +/- 6.0% of the dose was excreted in urine and 19.2 +/- 4.6% in feces. In 0-24-hr urine, unchanged drug was excreted (41.6% of the dose) as well as the unconjugated 4,5-dehydro metabolite (DHCBZ, 3.7%), conjugated p-hydroxybenzophenone (0.8%, only in one dog), and a phenolic metabolite, p-hydroxycibenzoline (HCBZ) in a rearranged form (RHCBZ) at 5.2% of the dose (free plus conjugated). Studies with synthetic HCBZ indicated that unrearranged HCBZ was excreted and that rearrangement occurred during purification. CBZ from dog urine displayed slight optical activity, based on ORD/CD data, corresponding to an optical purity of 15% of the S-(-)-CBZ, indicating a limited extent of stereoselective metabolism of CBZ in dogs. After an oral 50-mg/kg dose of 14C-CBZ succinate, male rats excreted in 3 days 27.0 +/- 2.8% in urine and 41.5 +/- 2.6% of the dose in feces, and in a repeated experiment 32.1 +/- 1.9% in urine and 54.5 +/- 0.7% in feces. CBZ (7.6%) and DHCBZ (0.2%) were determined in 0-24-hr urine, and CBZ (4.2%) and RHCBZ (4.2% of the dose) were determined in 0-24-hr feces. RHCBZ (3.1%), m-methoxy p-hydroxycibenzoline (8.3%), and p-hydroxybenzophenone (5.3% of the dose) were identified as glucuronide/sulfate conjugates in bile from rats. Evidence that p-hydroxybenzophenone arose from an unstable unidentified metabolite is discussed.     

Metabolism and disposition of a potent and selective JNK inhibitor [14C]tanzisertib following oral administration to rats,dogs and humans

Abstract

1. The disposition of tanzisertib [(1S,4R)-4-(9-((S)tetrahydrofuran-3-yl)-8-(2,4,6-trifluorophenylamino)-9H-purin-2-ylamino) cyclohexanol], a potent, orally active c-Jun amino-terminal kinase inhibitor intended for treatment of fibrotic diseases was studied in rats, dogs and humans following a single oral dose of [¹⁴C]tanzisertib (Independent Investigational Review Board Inc., Plantation, FL).

2. Administered dose was quantitatively recovered in all species and feces/bile was the major route of elimination. Tanzisertib was rapidly absorbed (T_max: 1–2?h) across all species with unchanged tanzisertib representing >83% of plasma radioactivity in dogs and humans, whereas <34% was observed in rats. Variable amounts of unchanged tanzisertib (1.5–32% of dose) was recovered in urine/feces across all species, the highest in human feces.

3. Metabolic profiling revealed that tanzisertib was primarily metabolized via oxidation and conjugation pathways, but extensively metabolized in rats relative to dogs/humans. CC-418424 (S-cis isomer of tanzisertib) was the major plasma metabolite in rats (38.4–46.4% of plasma radioactivity), while the predominant plasma metabolite in humans and dogs was M18 (tanzisertib-/CC-418424 glucuronide), representing 7.7 and 3.2% of plasma radioactivity, respectively. Prevalent biliary metabolite in rats and dogs, M18 represented 16.8 and 17.1% of dose, respectively.

4. In vitro studies using liver subcellular fractions and expressed enzymes characterized involvement of novel human aldo-keto reductases for oxido-reduction and UDP-glucuronosyltransferases for conjugation pathways.     

Characterization of ADME properties of [14C]asunaprevir (BMS-650032) in humans

1.?Asunaprevir (ASV, BMS-650032), a highly selective and potent NS3 protease inhibitor, is currently under development for the treatment of chronic hepatic C virus infection. This study describes in vivo biotransformation in humans and the identification of metabolic enzymes of ASV.

2.?Following a single oral dose of [¹⁴C]ASV to humans, the majority of radioactivity (>73% of the dose) was excreted in feces with <1% of the dose recovered in urine. Drug-related radioactivity readily appeared in circulation and the plasma radioactivity was mainly attributed to ASV. A few minor metabolites were observed in human plasma and are not expected to contribute to the pharmacological activity because of low levels. The area under the curve (AUC) values of each circulating metabolite in humans were well below their levels in animals used in the long-term toxicological studies. In bile and feces, intact ASV was a prominent radioactive peak suggesting that both metabolism and direct excretion played important roles in ASV clearance.

3.?The primary metabolic pathways of ASV were hydroxylation, sulfonamide hydrolysis and the loss of isoquinoline. In vitro studies with human cDNA expressed CYP enzymes and with human liver microsomes (HLM) in the presence of selective chemical inhibitors demonstrated that ASV was primarily catalyzed by CYP3A4 and CYP3A5.     

Biotransformation of carbon-14-labeled muraglitazar in male mice: interspecies difference in metabolic pathways leading to unique metabolites.

Muraglitazar (Pargluva; Bristol-Myers Squibb), a dual alpha/gamma peroxisome proliferator-activated receptor activator, is under development for treatment of type 2 diabetes. This study describes the biotransformation profile of carbon-14-labeled muraglitazar in plasma, urine, feces, and bile samples from male CD-1 mice [intact and bile duct cannulation (BDC)] after single oral doses of 1 and 40 mg/kg. The major drug-related component circulating in mouse plasma was the parent compound for up to 4 h postdose. Similar to excretion profiles of muraglitazar in humans, monkeys, and rats, urinary excretion was the minor and fecal excretion via the biliary route was the major elimination pathway for muraglitazar in mice. The parent compound was a minor component in urine, bile, and feces, indicating that muraglitazar was extensively metabolized in mice. Major biotransformation pathways of muraglitazar in mice included taurine conjugate formation, acyl glucuronidation, hydroxylation, and O-dealkylation. In addition to those metabolites previously identified in humans, monkeys, and rats (M1-M21), several unique metabolites identified in mice included taurine conjugates (M24, M25, M26a,b,c, and M31), oxazole-ring-opened metabolites (M27 and M28), glutathione conjugates (M29a,b and M30), a dihydroxylated metabolite (M32), hydroxylated metabolites (M33 and M35), and a dehydrogenated metabolite (M34). The taurine conjugate of muraglitazar, M24, was a major metabolite in mice, accounting for 12 to 15% of the total dose in BDC mice or 7 to 12% of the total dose in intact mice. None of these taurine and glutathione conjugates were found in the bile samples of humans, monkeys, or rats.