Metabolism of the carcinogen 7-methylbenz[c]-acridine in the rat

The biliary excretion of radioactivity by adult Wistar rats given i.v. 7-methyl-[7-14C]benz[c]acridine(14C-7-MBAC) and [methyl-3H]-7-methylbenz[c]acridine (3H-7-MBAC) (2 mg/kg) was 61% and 48%, respectively, in males in six hours. Females excreted 33% of a 2 mg/kg dose of 3H-7-MBAC in the same time-period. For male rats, the urinary and faecal excretions were about 10% and 61% of the dose of 14C-7-MBAC, respectively, in seven days. No enterohepatic circulation could be demonstrated in control male rats. The biliary excretion of radioactivity by phenobarbital- and 3-methylcholanthrene-induced male rats given 14C-7-MBAC was similar to or greater than that of control male rats. The organo-soluble biliary metabolites after beta-glucuronidase/arylsulphatase hydrolysis were separated by h.p.l.c., and quantitative metabolite distributions were obtained for induced and control rats by comparison with metabolite standards. The mutagenicity of bile from carcinogen-dosed control rats was greater than that of equivalent bile from carcinogen-dosed 3-methylcholanthrene-pretreated animals.     

Sex differences in the metabolism and excretion of nilvadipine,a new dihydropyridine calcium antagonist,in rats

1. The metabolic profiles of nilvadipine in the urine and bile of male and female rats were studied after i.v. dosing with 1?mg/kg of the ¹⁴C-labelled compound.

2. Excretion rates of the dosed radioactivity in male and female rats, respectively, in the first 48?h were 8.41% and 59.1% in bile, 12.0% and 36.9% in urine, and 2.5% and 3.6% in faeces.

3. Comparison of biliary and urinary excretion for each radioactive metabolite after dosing with ¹⁴C-nilvadipine, showed marked sex-related differences in the excretion routes of several metabolites. In male rats, metabolite M3, having a free 3-carboxyl group on the pyridine ring, was not excreted in urine, but in female rats urinary excretion of M3 accounted for 4.7% of the dose. One reason for the lower urinary excretion of radioactivity by males than by females was that the main metabolite, M3, was not excreted in the urine of the male rats.

4. To clarify the sex difference in the route of excretion of M3, this metabolite (M3) was given i.v. to rats. No excretion of the metabolite was observed in urine of male rats within 24?h but, in marked contrast, 41.5% of the dose was excreted in urine of females in the same period.     

Metabolism and disposition of gemfibrozil in Wistar and multidrug resistance-associated protein 2-deficient TR− rats

1. The roles of multidrug resistance-associated protein (Mrp) 2 deficiency and Mrp3 up-regulation were evaluated on the metabolism and disposition of gemfibrozil.

2. Results from in vitro studies in microsomes showed that the hepatic intrinsic clearance (CL_int) for the oxidative metabolism of gemfibrozil was slightly higher (1.5-fold) in male TR^? rats, which are deficient in Mrp2, than in wild-type Wistar rats, whereas CL_int for glucuronidation was similar in both strains.

3. The biliary excretion of intravenously administered [¹⁴C]gemfibrozil was significantly impaired in TR^? rats compared with Wistar rats (22 versus 93% of the dose excreted as the acyl glucuronides over 72?h). Additionally, the extent of urinary excretion of radioactivity was much higher in TR^? than in Wistar rats (78 versus 2.6% of the dose).

4. There were complex time-dependent changes in the total radioactivity levels and metabolite profiles in plasma, liver and kidney, some of which appeared to be related to the up-regulation of Mrp3.

5. Overall, it was demonstrated that alterations in the expression of the transporters Mrp2 and Mrp3 significantly affected the excretion as well as the secondary metabolism and distribution of [¹⁴C]gemfibrozil.     

The metabolism and disposition of [2-14C]diazepam in the streptozotocin-diabetic rat

1. The oral administration of [2-¹⁴C]diazepam to streptozotocin (STZ)-diabetic rats resulted in decreased faecal and biliary levels of metabolites with a concomitant rise in urinary radioactivity when compared to control values. This situation was reversible upon insulin treatment.

2. The increased urinary metabolite excretion could not be ascribed to the diuresis observed in STZ-diabetic rats.

3. No alteration in the phase I or II routes of [¹⁴C]diazepam metabolism in diabetic animals was observed either in vivo or in vitro.

4. Following i.v. administration of [2-¹⁴C]diazepam, blood ¹⁴C levels in diabetic rats were elevated above those observed in normal animals.     

The Fate of 2,6-Dimethoxy[U-14C]phenol in the Rat

Abstract

1. The metabolic fate of 2,6-dimethoxy[U-¹⁴C]phenol, administered intravenously to rats at three dose levels (10–30 mg/kg body wt.), was investigated.

2. The majority of injected radioactivity appeared in urine but significant amounts were eliminated via the bile (16.3–35.4%).

3. The urinary radioactivity was associated with two metabolites identified as 2,6-dimethoxy[U-¹⁴C]phenylglucuronide and 2,6-dimethoxy[U-¹⁴C]phenylsulphate. The glucuronide conjugate predominated in the female rat while approximately equal amounts of the conjugates were produced by the male.

4. The biliary metabolite was identified as 2,6-dimethoxy[U-¹⁴C]phenyl-glucuronide.     

Studies on Metabolism of Trazodone,I. Metabolic Fate of [14C]Trazodone Hydrochloride in Rats

Abstract

1. One of the main metabolites of [¹⁴C]trazodone hydrochloride by rat liver in vitro is hydroxylated trazodone.

2. [¹⁴C]Trazodone HCI is absorbed very rapidly and the blood level of radioactivity attains a maximum within 15 min after oral administration of 4 mg/kg to rats and thereafter decreases rapidly.

3. Urinary and faecal excretions of radioactivity are 49.0 and 46.1% of the dose respectively, during the first 7 days after ingestion, and biliary excretion is 80.0% in 8 h.

4. After oral administration of [¹⁴C]trazodone HCI to rats the main metabolites in urine and bile are hydroxylated trazodone, β-{3-oxo-s-triazolo[4,3a]-pyridin-2-yl}-propionic acid and their glucuronides.

5. Unchanged and hydroxylated trazodone alone are present in brain of rats after oral administration (20 mg/kg); both compounds in brain decrease with similar half-lives to those in plasma.     

Comparative Studies on the Metabolic Disposition of 8-Chloro-6-pheny1–4H-s-triazolo[4,3-a][1,4]benzo-diazepine (D-40TA) and Nitrazepam after Single and Repeated Administration in Rats

Abstract

1. Orally administered D-40TA was absorbed by rats with a maximum blood level at 30 min and a half-life of 60 min. The blood level of orally administered nitrazepam reached a plateau which persisted for 90 min and then declined with a half-life of 90 min.

2. Both D-40TA and nitrazepam crossed the blood-brain barrier of rats. The 1-oxo metabolite of D-40TA is pharmacologically active, and also readily entered the brain.

3. Orally administered D-40TA and nitrazepam were eliminated in urine and faeces over 3 days, the larger part in faeces. In both cases, about 90% of the dose of radioactivity was eliminated from the body during the first 2 days after administration.

4. After intravenous injection of either [¹⁴C]D-40TA or [¹⁴C]nitrazepam, the radioactivity was excreted in bile at the same rate, 69 and 64% of the dose being recovered from the 24 h-bile, respectively. The biliary metabolites of both benzodiazepines underwent entero-hepatic cycling.

5. After daily oral administration of [¹⁴C]D-40TA or [¹⁴C]nitrazepam, the cumulative excretion closely paralleled the dosage of radioactivity. For both drugs, excretion was complete within 3 days of discontinuing medication. During repeated administrations of the labelled drugs, no increase in concn. of blood radioactivity 1 h after dosing was observed. With [¹⁴C]D-40TA-treated rats, most of the radioactivity still in the body 24 h after administration was recovered from the gastro-intestinal contents; only small amounts were in tissues. Dosing of [¹⁴C]D-40TA for 7 days caused no increase in tissue levels of radioactivity, except in the liver, where the radioactivity increased to about twice the level noted after a single administration.     

Metabolism of Linoleamides: II. Absorption,Distribution, Excretion and Metabolism of N-[α-Phenyl-β-(p-tolyl)ethyl] linoleamide

1. Absorption, distribution, excretion and metabolism of (-)N-[α-phenyl-β-(p-tolyl)ethyl][¹⁴C]linoleamide (¹⁴C-PTLA) were studied in rats and dogs. Faecal excretion of PTLA was studied in dogs and men by g.l.c.

2. ¹⁴C-PTLA (10 mg/kg) given orally to rats resulted in urinary and faecal excretion of radioactivity of 2 and 93 %, respectively, by male rats and 8 and 87% by female rats in 48 h. Faecal excretion of PTLA in men was similar to that in rats.

3. Distribution of radioactivity in rats and dogs after oral administration of ¹⁴C-PTLA showed that a major part of the dose was not absorbed.

4. N-[α-Phenyl-β-(p-tolyl)ethyl]succinic acid monoamide and N-[α-phenyl-β-(p-tolyl)ethyl]glutaric acid monoamide were detected in the urine of rats dosed orally with ¹⁴C-PTLA.     

Metabolism,excretion and pharmacokinetics of [14C]glasdegib (PF-04449913) in healthy volunteers following oral administration

1.?The metabolism, excretion and pharmacokinetics of glasdegib (PF-04449913) were investigated following administration of a single oral dose of 100?mg/100 μCi [¹⁴C]glasdegib to six healthy male volunteers (NCT02110342).

2.?The peak concentrations of glasdegib (890.3?ng/mL) and total radioactivity (1043 ngEq/mL) occurred in plasma at 0.75?hours post-dose. The AUC_inf were 8469?ng.h/mL and 12,230 ngEq.h/mL respectively, for glasdegib and total radioactivity.

3.?Mean recovery of [¹⁴C]glasdegib-related radioactivity in excreta was 91% of the administered dose (49% in urine and 42% in feces). Glasdegib was the major circulating component accounting for 69% of the total radioactivity in plasma. An N-desmethyl metabolite and an N-glucuronide metabolite of glasdegib represented 8% and 7% of the circulating radioactivity, respectively. Glasdegib was the major excreted component in urine and feces, accounting for 17% and 20% of administered dose in the 0–120?hour pooled samples, respectively. Other metabolites with abundance <3% of the total circulating radioactivity or dose in plasma or excreta were hydroxyl metabolites, a desaturation metabolite, N-oxidation and O-glucuronide metabolites.

4.?Elimination of [¹⁴C]glasdegib-derived radioactivity was essentially complete, with similar contribution from urinary and fecal routes. Oxidative metabolism appears to play a significant role in the biotransformation of glasdegib.     

Role of the intestinal microflora in clonazepam metabolism in the rat

1. The metabolism of clonazepam was studied in vitro and in vivo using germ-free and ex-germ-free rats.

2. Incubation of clonazepam with rat-intestinal lumen contents gave nearly complete reduction of clonazepam to 7-aminoclonazepam. Rat-hepatic microsomes also reduced clonazepam but only under anaerobic conditions. Aerobic microsomal incubations gave 3-hydroxyclonazepam as the predominant metabolite. Both aerobic and anaerobic microsomal metabolism were induced by phenobarbital. Carbamazepine pretreatment significantly induced only 3-hydroxylation slightly; whereas β-naphthoflavone had no significant effect.

3. Extensive biliary disposition of hydroxylated clonazepam metabolites into the gut occurred. Only very low levels of clonazepam were found in bile. Using a linked-rat procedure enterohepatic recirculation of biliary metabolites was demonstrated and suppression (antibiotic treatment) or absence (germ-free) of the gut microflora nearly eliminated recycling.

4. Following oral administration of [¹⁴C]clonazepam to germ-free rats, reduced metabolites accounted for 15% of the radioactivity in the urine, with over 70% of the ¹⁴C attributed to a phenolic clonazepam metabolite. In contrast 77% of the recovered metabolites were derived from nitroreduction in the same animals following acquisition of an intestinal microflora; 7-acetamidoclonazepam was the major metabolite in these ex-germ-free animals. These studues show that clonazepam metabolism is primarily reductive in the presence of gut flora and oxidative in its absence.     

Absorption,metabolism and excretion of cobimetinib,an oral MEK inhibitor,in rats and dogs

1.?The absorption, metabolism and excretion of cobimetinib, an allosteric inhibitor of MEK1/2, was characterized in mass balance studies following single oral administration of radiolabeled (¹⁴C) cobimetinib to Sprague–Dawley rats (30?mg/kg) and Beagle dogs (5?mg/kg).

2.?The oral dose of cobimetinib was well absorbed (81% and 71% in rats and dogs, respectively). The maximal plasma concentrations for cobimetinib and total radioactivity were reached at 2–3?h post-dose. Drug-derived radioactivity was fully recovered (～90% of the administered dose) with the majority eliminated in feces via biliary excretion (78% of the dose for rats and 65% for dogs). The recoveries were nearly complete after the first 48?h following dosing.

3.?The metabolic profiles indicated extensive metabolism of cobimetinib prior to its elimination. For rats, the predominant metabolic pathway was hydroxylation at the aromatic core. Lower exposures for cobimetinib and total radioactivity were observed in male rats compared with female rats, which was consistent to in vitro higher clearance of cobimetinib for male rats. For dogs, sequential oxidative reactions occurred at the aliphatic portion of the molecule. Though rat metabolism was well-predicted in vitro with liver microsomes, dog metabolism was not.

4.?Rats and dogs were exposed to the two major human circulating Phase II metabolites, which provided relevant metabolite safety assessment. In general, the extensive sequential oxidative metabolism in dogs, and not the aromatic hydroxylation in rats, was more indicative of the metabolism of cobimetinib in humans.     

Identification of the metabolites of irinotecan,a new derivative of camptothecin,in rat bile and its biliary excretion

1. To investigate the metabolites and biliary excretion of new camptothecin analogue, irinotecan, the drug was administered i.v. to rats (10?mg/kg) and bile, urine and faeces were collected.

2. In rat bile, unchanged irinotecan, the metabolite 7-ethyl-10-hydroxycamptothecin (EHCPT) and unknown metabolite M-1 were found by t.l.c. and?h.p.l.c. From β-glucuronidase hydrolysis, n.m.r. spectrometry and mass spectrometry, M-1 was identified as EHCPT-glucuronide (EHCPT Glu). Other metabolites in the bile were negligible.

3. The cumulative biliary and urinary excretion of radioactivity after dosage of rats with irinotecan were 62.2% and 33.3% dose, respectively, and 9.0% of the radioactivity was excreted in the faeces.

4. Approx. 55% of the biliary radioactivity excreted in 24?h was unchanged irinotecan, 22% was EHCPT Glu, and 9% was EHCPT.

5. Approx. 18% of the biliary radioactivity was reabsorbed from the intestine.     

2-Chloroacetaldehyde,a metabolite of cyclophosphamide in the rat

1. Following simultaneous i.v. administration of a mixture of [4-¹⁴C]cyclophosphamide (¹⁴C-CP) and [side-chain³H]CP to rats, a metabolite containing predominantly ³H radioactivity was excreted in the urine.

2. The ³H-labelled urinary metabolite was identified as 2-chloroacetaldehyde.

3. Chloro[³H]acetaldehyde accounted for approx. 3.8% of urinary³H radioactivity.

4. The importance of chloroacetaldehyde as a toxic metabolite of CP is discussed. particularly in relation to haemorrhagic bladder disease.     

Absorption,Metabolism, and Excretion of 2,3:4,5-Bis(2-Butylene) Tetrahydro-2 Furaldehyde (Mgk R11)in the Rat

Abstract

Experiments were conducted in four groups of rats to determine the absorption, distribution, metabolism, and excretion (ADME) patterns following oral administration of [formyl-¹⁴C] 2,3:4,5-bis(2-butylene) tetrahydro-2 furaldehyde (MGK R11).

Ten rats (five males and five females) were used in each of the four experiments. Fasted rats were administered [for-myl-¹⁴C] MGK R11 at a single oral dosage of 65 mg/kg, at a single oral dosage of 1000 mg/kg, and at a daily oral dosage of 65 mg/kg of nonradiolabeled compound for 14 days followed by a single dose of ¹⁴C-labeled compound at 65 mg/kg. Rat blood kinetics were determined in the fourth group following a single oral dose of 65 mg/ kg. Each animal was administered approximately 12–14 μCi of radioactivity.

Urine and feces were collected from all groups at predetermined time intervals. Seven days after dose administration, the rats were euthanized and selected tissues and organs were harvested. Samples of urine, feces, and tissues were subsequently analyzed for ¹⁴C content.

In the blood kinetics study, radioactivity peaked at approximately 30 min in both the males and females, indicating very rapid absorption. The decline of radioactivity from blood followed a biphasic elimination pattern. The first half-life was 1.36 h for males and 1.18 h for females. In the second phase, the half-life was 21 h for males and 26 h for females.

Female rats excreted 67.21-86.85% of the radioactivity in urine and 13.99–28.08% in feces, whereas male rats excreted 50.19–64.37% of the administered radioactivity in urine and 31.43–40.94% in feces. Tissue residues of ¹⁴C ranged between 0.47% and 1.09% of the administered dose. The total mean recovered radioactivity of the administered dose in the four definitive studies ranged between 92% and 101%. No parent compound was detected in the urine.

Three major and one minor metabolite was isolated by high-performance liquid chromatography (HPLC) and identified by gas chromatography/mass spectrometry (GC/MS). One major metabolite was formed by oxidation of the aldehyde moiety to the carboxylic acid. A second metabolite was the glucuronic acid conjugate of the carboxylic acid and the third was formed by reduction of the aldehyde moiety of MGK R11 to an alcohol followed by glucuronic acid conjugation. The minor metabolite was the unconjugated alcohol derivative of MGK R11.

The gender of the animals affected the rate, route of excretion, and metabolic profile. The urinary excretion rate was faster in females than in males and the amount excreted was also greater in female rats.     

The Metabolism of Tolamolol* in the Mouse,Rat, Guinea-pig,Rabbit and Dog

1. [³H, ¹⁴C]Tolamolol was well absorbed after oral administration to mice, rats, guinea-pigs, rabbits and dogs.

2. The major route for excretion of. radioactivity by mice, rats and guineapigs was the faeces; in rabbits the major route was the urine. Dogs excreted similar amounts of radioactivity by both routes. Biliary excretion of radioactivity by the rat and guineapig was demonstrated.

3. Tolamolol was extensively metabolized by all five species. The major metabolite in mice, rats, guinea-pigs and rabbits was the product of hydroxylation of the tolyl ring, which was excreted as such and as the glucuronide and sulphate conjugates.

4. In the dog the major metabolite was the acid resulting from hydrolysis of the carbamoyl group. This acid was also excreted by the rabbit, but was only a minor metabolite in the other species studied.     

Pharmacokinetics and metabolism of α-[(dimethylamino)methyl]-2-(3-ethyl-5-methyl-4-isoxazolyl)-1H-indole-3-methanol,a hypoglycemic agent,in man

1. The pharmacokinetics and metabolism of α-[(dimethylamino)methyl]-2-(3-ethyl-5-methyl-4-isoxazolyl)-1H-[3-¹⁴C] indole-3-methanol, a new hypoglycemic agent, have been studied in 15 healthy male volunteers who received an oral dose of 50 or 200 mg.

2. The drug was rapidly and almost completely absorbed intact from the gastrointestinal tract.

3. Compared with the 50 mg dose, the 200 mg dose yielded less than proportionally higher blood concentrations of radioactivity and unchanged drug. This phenomenon has been observed previously in the rat and was probably due to an increase in drug distribution volume with increasing dose, since the metabolism and excretion patterns of the drug appeared to be dose-independent.

4. The drug was partially metabolized prior to excretion. Approximately 40% of the dose was recovered intact, almost exclusively in urine. The major metabolic pathway of the drug was by conjugation with glucuronic acid, while oxidation of the indole ring gave rise to a relatively minor metabolite.

5. The recovery of administered radioactivity was virtually complete within the experimental period, with a renal: faecal excretion ratio of ca 80: 20. The elimination half-life of unchanged drug was 25-30h while that of total radioactivity was 33-35 h.     

Metabolism and excretion of [14C]taranabant,a cannabinoid-1 inverse agonist,in humans

1. Taranabant (N-[(1S,2S)-3-(4-Chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-{[5-(trifluoromethyl)pyridin-2-yl]oxy}propanamide or MK-0364) is an orally active inverse agonist of the cannabinoid 1 (CB-1) receptor that was under development for the management of obesity. The metabolism and excretion of taranabant were investigated following a single oral dose of 5?mg/201 μCi [¹⁴C]taranabant to six healthy male subjects. The overall excretion recovery of the administered radioactivity was nearly quantitative (～?92%), with the majority of the dose (～?87%) excreted into faeces and a much smaller fraction (～?5%) into urine.

2. Taranabant was absorbed rapidly, with C_max of radioactivity attained at 1–2-h postdose. The parent compound and its monohydroxylated metabolite, M1, were the major radioactive components circulating in plasma and comprised ～?12–24% and 33–42%, respectively, of the plasma radioactivity for up to 48?h. A second monohydroxylated metabolite, designated as M1a, represented ～?10–12% of the radioactivity in the 2- and 8-h postdose plasma profiles.

3. Metabolite profiles of the faeces samples consisted mainly of the (unabsorbed) parent compound and multiple diastereomeric carboxylic acid derivatives derived from oxidation of the geminal methyl group of the parent compound and of the hydroxylated metabolite/s. These data suggest that, similar to rats and monkeys, taranabant is primarily eliminated in humans via oxidative metabolism and excretion of metabolites via the biliary/faecal route.

     

Studies on the Biliary Excretion and Metabolites of the Antioxidant Ethoxyquin, 6-Ethoxy-2,2,4-Trimethyl-1,2-Dihydroquinoline in the Rat

1. Biliary excretion and metabolites of ethoxyquin, and gastro-intestinal absorption of ethoxyquin were studied in rat.

2. An average of 28 and 36% of the dose of¹⁴C following intragastric administration of [¹⁴C]ethoxyquin was recovered in the bile of bile-duct cannulated rats in 12 and 24?h, respectively.

3. By g.l.c.-mass spectrometry, 75 to 85% of the ¹⁴C excreted in the 12?h bile was identified as unchanged ethoxyquin, and the following metabolites were isolated and identified: 8-hydroxy-ethoxyquin, hydroxylated 8-hydroxy-ethoxyquin, 6-ethoxy-2,2,4-trimethyl-8-quinolone, hydroxylated 6-ethoxy-2,2,4-trimethyl-8-quinolone, 6-ethoxy-2,4-dimethylquinoline and 2,2,4-trimethyl-6-quinolone.

4. Three groups of rats were used in the biliary excretion experiments, and the effect of standardization of experimental conditions was demonstrated. Infusion of sodium tauro-cholate following bile-duct cannulation did not affect the biliary excretion kinetics of ethoxyquin.

5. Only about 3% of the radioactivity administered was absorbed from the gastrointestinal tract via the lymphatic pathway in thoracic-duct cannulated rats within 24?h. It was concluded that ethoxyquin was absorbed primarily by the portal route.     

Toxicokinetics of 4-methylimidazole in the male F344 rat

1. The toxicokinetics and metabolism of 4-methylimidazole (4-MZ) have been studied in the male F344 rat using ¹⁴C radiolabelled compound. Radioactivity in plasma and urine was profiled by hplc.

2. After gavage administration of 50?mg/kg, about 85% of the administered radioactivity was recovered in urine within 48?h. The majority of the radioactivity in urine or plasma was associated with the parent compound and only one minor hydrophilic metabolite was present in urine and in plasma. Elimination of radioactivity via fecal, biliary or respiration was negligible.

3. Elimination of 4-MZ after an i.v. dose of 5mg/kg can be described by a two-compartment process with an estimated half-life of 1.8?h and an estimated apparent volume of distribution of 2.3 litre/kg.

4. After gavage at doses of 5, 50 and 150?mg/kg, 4-MZ was readily absorbed with a estimated bioavailability of 60–70%.

5. Urinary excretion data indicated that renal clearance of 4-MZ accounted for about 80% of total body plasma clearance. Based on the estimated AUC of metabolite and the estimated renal clearance of 4-MZ, the formation of metabolite and the renal clearance of 4-MZ appeared to be a saturable process.     

Absorption,distribution, metabolism and excretion of gemigliptin,a novel dipeptidyl peptidase IV inhibitor,in rats

Abstract

1.?The absorption, distribution, metabolism and excretion of a novel dipeptidyl peptidase IV inhibitor, gemigliptin, were examined following single oral administration of ¹⁴C-labeled gemigliptin to rats.

2.?The ¹⁴C-labeled gemigliptin was rapidly absorbed after oral administration, and its bioavailability was 95.2% (by total radioactivity). Distribution to specific tissues other than the digestive organs was not observed. Within 7 days after oral administration, 43.6% of the administered dose was excreted via urine and 41.2% was excreted via feces. Biliary excretion of the radioactivity was about 17.7% for the first 24?h. After oral administration of gemigliptin to rats, the in vivo metabolism of gemigliptin was investigated with bile, urine, feces, plasma and liver samples.

3.?The major metabolic pathway was hydroxylation, and the major circulating metabolites were a dehydrated metabolite (LC15-0516) and hydroxylated metabolites (LC15-0635 and LC15-0636).