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.     

Biotransformation and mass balance of faldaprevir,a hepatitis C NS3/NS4 protease inhibitor in rats

Abstract

1.?The metabolism, pharmacokinetics, excretion and tissue distribution of a hepatitis C NS3/NS4 protease inhibitor, faldaprevir, were studied in rats following a single 2?mg/kg intravenous or 10?mg/kg oral administration of [¹⁴C]-faldaprevir.

2.?Following intravenous dosing, the terminal elimination t_1/2 of plasma radioactivity was 1.75?h (males) and 1.74?h (females). Corresponding AUC_0–∞, CL and V_ss were 1920 and 1900?ngEq?·?h/mL, 18.3 and 17.7?mL/min/kg and 2.32 and 2.12?mL/kg for males and females, respectively.

3.?After oral dosing, t_1/2 and AUC_0–∞ for plasma radioactivity were 1.67 and 1.77?h and 11?300 and 17?900 ngEq?·?h/mL for males and females, respectively.

4.?In intact rats, ≥90.17% dose was recovered in feces and only ≤1.08% dose was recovered in urine for both iv and oral doses. In bile cannulated rats, 54.95, 34.32 and 0.27% dose was recovered in feces, bile and urine, respectively.

5.?Glucuronidation plays a major role in the metabolism of faldaprevir with minimal Phase I metabolism.

6.?Radioactivity was rapidly distributed into tissues after the oral dose with peak concentrations of radioactivity in most tissues at 6?h post-dose. The highest levels of radioactivity were observed in liver, lung, kidney, small intestine and adrenal gland.     

Pharmacokinetics of the selective prostacyclin receptor agonist selexipag in rats,dogs and monkeys

1.?This study examined the pharmacokinetics, distribution, metabolism and excretion of the selective prostacyclin receptor agonist selexipag (NS-304; ACT-293987) and its active metabolite MRE-269 (ACT-33679). The compounds were investigated following oral and/or intravenous administration to intact rats, dogs and monkeys, and bile-duct-cannulated rats and dogs.

2.?After oral administration of [¹⁴C]selexipag, selexipag was well absorbed in rats and dogs with total recoveries of over 90% of the dose, mainly in the faeces. Biliary excretion was the major elimination pathway for [¹⁴C]MRE-269 as well as [¹⁴C]selexipag, while renal elimination was of little importance. [¹⁴C]Selexipag-related radioactivity was secreted into the milk in lactating rats.

3.?Plasma was analysed for total radioactivity, selexipag and MRE-269 in rats and monkeys. Selexipag was negligible in rat plasma due to extensive metabolism, and MRE-269 was present in rat and monkey plasma. A species difference was clearly evident when selexipag was incubated in rat, dog and monkey plasma.

4.?Total radioactivity was rapidly distributed to tissues. The highest concentrations were found in the bile duct and liver without significant accumulation or persistence, while there was limited melanin-associated binding, penetration of the blood–brain barrier and placental transfer of drug-related materials.     

Disposition of a new tetrahydrocarbazole analgesic drug in laboratory animals and man

1. The disposition of AY-30,068 (I), a new tetrahydrocarbazole analgesic drug, was studied in mice, rats, dogs, rhesus monkeys, and man.

2. Oral doses of the ¹⁴C-labelled drug in aqueous solution were well absorbed in rodents, but absorption of oral doses of the crystalline drug in dogs was poor. Due to the virtual absence of serum metabolites in rats and dogs, the bioavailability of I was nearly identical to the extent of absorption. Although a small first-pass effect was observed in mice, unchanged I represented a major portion of serum radioactivity.

3. A linear increase in the serum concentrations of I occurred at doses between 0.05 and 25?mg/kg in rats, 0.1 and 50?mg/kg in dogs, and 1–160?mg in man. In rhesus monkeys given a 0.5?mg/kg oral dose, the C_max and AUC of I were similar to values obtained following a corresponding dose in dogs.

4. After i.v. administration of a 1.0?mg/kg dose the terminal elimination half-life (t1/2β) of I was 4?h in mice and 9–10h in rats and dogs. In rodents, dogs, and several human subjects, the elimination of I was interrupted by secondary peaks. Enterohepatic circulation was confirmed in bile duct cannulated rats, where the t1/2β of I was decreased to 2.4?h. In rodents the serum clearance and apparent volume of distribution of I were 0.04–0.21/kg.?h and 0.5–0.81/kg, respectively, and 0.61/kg.h and 9.81/kg in dogs.

5. In rodents and dogs dosed with ¹⁴C-labelled I, radioactivity was excreted almost entirely in the faeces. No unchanged I was detected in rat bile, while about 70% of the radioactivity corresponded to conjugates of parent drug.     

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).     

The comparative disposition and metabolism of dolutegravir,a potent HIV-1 integrase inhibitor,in mice,rats, and monkeys

Abstract

1.?Plasma clearance of dolutegravir, an unboosted HIV-1 integrase inhibitor, was low in rat and monkey (0.23 and 2.12?mL/min/kg, respectively) as was the volume of distribution (0.1 and 0.28?L/kg, respectively) with terminal elimination half-life approximately 6?h. Dolutegravir was rapidly absorbed from oral solution with a high bioavailability in rat and monkey (75.6 and 87.0% respectively), but solubility or dissolution rate limited when administered as suspension.

2.?Dolutegravir was highly bound (>99%) to serum proteins in rat and monkey, similar to binding to plasma and serum proteins in human. Radioactivity was associated with the plasma versus cellular components of blood across all species.

3.?Following oral administration to rats, [¹⁴C]dolutegravir-related radioactivity was distributed to most tissues, due in part to high permeability; however, because of high plasma protein binding, tissue to blood ratios were low. In mouse, rat and monkey, the absorbed dose was extensively metabolized and secreted into bile, with the majority of the administered radioactivity eliminated in feces within 24?h.

4.?The primary route of metabolism of dolutegravir was through the formation of an ether glucuronide. Additional biotransformation pathways: benzylic oxidation followed by hydrolysis to an N-dealkylated product, glucose conjugation, oxidative defluorination, and glutathione conjugation.     

Disposition and pharmacokinetics of temozolomide in rat

1.?Temozolomide, an imidazotetrazine derivative, is a cytotoxic alkylating agent of broad-spectrum antitumour activity. The absorption, metabolism, distribution and excretion of temozolomide have been investigated in male and female Sprague–Dawley and Long–Evans rats following single oral or intravenous dose administration of 200?mg?m^?2 non-radiolabelled or ¹⁴C-radiolabelled temozolomide. The distribution of ¹⁴C-temozolomide was also evaluated by whole-body autoradiography in male Sprague–Dawley rats. Plasma concentrations of temozolomide and its active metabolite 3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC) were determined by high-performance liquid chromatography (HPLC) with ultraviolet detection. Plasma, urine and faeces were profiled by HPLC with radiochemical detection.

2.?Temozolomide was rapidly and extensively (>90%) absorbed and widely distributed in tissues. The distribution pattern of radioactivity was gender independent. Penetration into the brain following oral or intravenous administration was 35–39% based on the brain/plasma AUC ratio.

3.?Following intravenous or oral administration, temozolomide was primarily eliminated renally (75–85% of the dose) as either unchanged drug, a carboxylic acid analogue, AIC (a degradation product) and a highly polar unidentified peak. Biliary excretion was minimal (1.4–1.6%). The pharmacokinetics (oral versus intravenous) were similar and gender independent. The absolute oral availability was 96–100%. Temozolomide was rapidly eliminated (t_1/2 = 1.2?h) and converted to MTIC.

4.?Systemic exposure to MTIC was about 2% that of temozolomide. Overall, the disposition of temozolomide in rats was similar to that observed in humans.     

Pharmacokinetics and metabolism of [14C]-tozadenant (SYN-115), a novel A2a receptor antagonist ligand,in healthy volunteers

1.?This phase-I study (NCT02240290) was designed to investigate the human absorption, disposition and mass balance of ¹⁴C-tozadenant, a novel A2a receptor antagonist in clinical development for Parkinson s disease.

2.?Six healthy male subjects received a single oral dose of tozadenant (240?mg containing 81.47?KBq of [¹⁴C]-tozadenant). Blood, urine and feces were collected over 14 days. Radioactivity was determined by liquid scintillation counting or accelerator mass spectrometry (AMS). Tozadenant and metabolites were characterized using HPLC-MS/MS and HPLC-AMS with fraction collection.

3.?At 4?h, the C_max of tozadenant was 1.74?μg/mL and AUC_(0–t) 35.0?h?μg/mL, t_1/2 15?h, Vz/F 1.82?L/kg and CL/F 1.40?mL/min/kg. For total [¹⁴C] radioactivity, the C_max was 2.29?μg?eq/mL at 5?h post-dose and AUC_(0–t) 43.9?h?μg?eq/mL. Unchanged tozadenant amounted to 93% of the radiocarbon AUC_(0–48h). At 312?h post-dose, cumulative urinary and fecal excretion of radiocarbon reached 30.5% and 55.1% of the dose, respectively. Unchanged tozadenant reached 11% in urine and 12% of the dose in feces. Tozadenant was excreted as metabolites, including di-and mono-hydroxylated metabolites, N/O dealkylated metabolites, hydrated metabolites.

4.?The only identified species circulating in plasma was unchanged tozadenant. Tozadenant was primarily excreted in urine and feces in the form of metabolites.     

Absorption,distribution and excretion of the new thienopyridine agent prasugrel in rats

Prasugrel is converted to the pharmacologically active metabolite after oral dosing in vivo. In this study, ¹⁴C-prasugrel or prasugrel was administered to rats at a dose of 5?mg?kg^–1. After oral and intravenous dosing, the values of AUC_0–∞ of total radioactivity were 36.2 and 47.1?µg?eq.?h?ml^–1, respectively. Oral dosing of unlabeled prasugrel showed the second highest AUC_0–8 of the active metabolite of six metabolites analyzed. Quantitative whole body autoradiography showed high radioactivity concentrations in tissues for absorption and excretion at 1?h after oral administration, and were low at 72?h. The excretion of radioactivity in the urine and feces were 20.2% and 78.7%, respectively, after oral dosing. Most radioactivity after oral dosing was excreted in bile (90.1%), which was reabsorbed moderately (62.4%). The results showed that orally administered prasugrel was rapidly and fully absorbed and efficiently converted to the active metabolite with no marked distribution in a particular tissue.     

Pharmacokinetics of tafamidis,a transthyretin amyloidosis drug,in rats

1.?We characterized the pharmacokinetics of tafamidis, a novel drug to treat transthyretin-related amyloidosis, in rats after intravenous and oral administration at doses of 0.3–3?mg/kg. In vitro Caco-2 cell permeability and liver microsomal stability, as well as in vivo tissue distribution and plasma protein binding were also examined.

2.?After intravenous injection, systemic clearance (CL), volumes of distribution at steady state (V_ss) and half-life (T_½) remained unaltered as a function of dose, with values in the ranges of 6.41–7.03?mL/h/kg, 270–354?mL/kg and 39.5–46.9?h, respectively. Following oral administration, absolute bioavailability was 99.7–104% and was independent of doses from 0.3 to 3?mg/kg. In the urine and faeces, 4.36% and 48.9% of tafamidis, respectively, were recovered.

3.?Tafamidis was distributed primarily in the liver and not in the brain, kidney, testis, heart, spleen, lung, gut, muscle, or adipose tissue. Further, tafamidis was very stable in rat liver microsomes, and its plasma protein binding was 99.9%.

4.?In conclusion, tafamidis showed dose-independent pharmacokinetics with intravenous and oral doses of 0.3–3?mg/kg. Tafamidis undergoes minimal first-pass metabolism, distributes mostly in the liver and plasma, and appears to be eliminated primarily via biliary excretion.     

Metabolic disposition of gefitinib,an epidermal growth factor receptor tyrosine kinase inhibitor,in rat,dog and man

1.?Following oral administration of [¹⁴C]-gefitinib to albino and pigmented rats, radioactivity was widely and rapidly distributed, with the highest levels being found in liver, kidney, lung and gastrointestinal tract, but with only low levels penetrating the brain. Levels of radioactivity persisted in melanin-containing tissues (pigmented eye and skin).

2.?Binding to plasma proteins was high (86–94%) across the range of species examined and was 91% in human plasma. Substantial binding occurred to both human serum albumin and α-1 acid glycoprotein.

3.?Following oral and intravenous administration of [¹⁴C]-gefitinib, excretion of radioactivity by rat, dog and human occurred predominantly via the bile into faeces, with <7% of the dose being eliminated in urine.

4.?In all three species, gefitinib was cleared primarily by metabolism. In rat, morpholine ring oxidation was the major route of metabolism, leading to the formation of M537194 and M608236 as the main biliary metabolites. Morpholine ring oxidation, together with production of M523595 by O-demethylation of the quinazoline moiety, were the predominant pathways in dog, with oxidative defluorination also occurring to a lesser degree.

5.?Pathways in healthy human volunteers were similar to dog, with O-demethylation and morpholine ring oxidation representing the major routes of metabolism.     

Preclinical absorption,distribution, metabolism,excretion and pharmacokinetics of a novel selective inhibitor of breast cancer resistance protein (BCRP)

1.?Breast cancer resistance protein (BCRP) plays an important role in drug absorption, distribution and excretion. It is challenging to evaluate BCRP functions in preclinical models because commonly used BCRP inhibitors are nonspecific or unstable in animal plasma.

2.?In this work, in vitro absorption, distribution, metabolism and elimination (ADME) assays and pharmacokinetic (PK) experiments in Bcrp knockout (KO) (Abcg2^?/?) and wild-type (WT) FVB mice and Wistar rats were conducted to characterize the preclinical properties of a novel selective BCRP inhibitor (ML753286, a Ko143 analog).

3.?ML753286 is a potent inhibitor for BCRP, but not for P-glycoprotein (P-gp), organic anion-transporting polypeptide (OATP) or major cytochrome P450s (CYPs). It has high permeability, but is not an efflux transporter substrate. ML753286 has low to medium clearance in rodent and human liver S9 fractions, and is stable in plasma cross species. Bcrp inhibition affects oral absorption and clearance of sulfasalazine in rodents. A single dose of ML753286 at 50–300?mg/kg orally, and at 20?mg/kg intravenously or 25?mg/kg orally inhibits Bcrp functions in mice and rats, respectively.

4.?These findings confirm that ML753286 is a useful selective inhibitor to evaluate BCRP/Bcrp activity in vitro and in rodent model systems.     

Pharmacokinetics,metabolism, and excretion of cycloastragenol,a potent telomerase activator in rats

1.?The objective of this study was to investigate the pharmacokinetics, excretion, and metabolic fate of cycloastragenol (CA) in rats.

2.?An LC-MS method was developed and used to quantify CA in biological samples. Rats were orally administrated with CA at 10, 20, and 40?mg/kg or intravenously administrated at 10?mg/kg to determine pharmacokinetic parameters of CA. For excretion experiment, urine, feces, and bile were collected at 24?h after oral administration (40?mg/kg), also at 12?h after intravenous administration (10?mg/kg). An LC-MS/MS method was developed to identify the metabolites of CA.

3.?The results showed that the oral bioavailability of CA was about 25.70% at 10?mg/kg. CA was excreted through bile and feces and eliminated predominantly by the kidney in rats. It also might exist an enterohepatic circulation of CA in rats. CA could be metabolized widely in vivo in rat, seven, six, and one phase I metabolites were found in feces, urine, and bile samples respectively, but no phase II metabolite was found.

4.?In summary, this study defined pharmacokinetics characteristics of CA, described its excretion, and established its in vivo metabolism in rats.     

Clinical disposition,metabolism and in vitro drug–drug interaction properties of omadacycline

1.?Absorption, distribution, metabolism, transport and elimination properties of omadacycline, an aminomethylcycline antibiotic, were investigated in vitro and in a study in healthy male subjects.

2.?Omadacycline was metabolically stable in human liver microsomes and hepatocytes and did not inhibit or induce any of the nine cytochrome P450 or five transporters tested. Omadacycline was a substrate of P-glycoprotein, but not of the other transporters.

3.?Omadacycline metabolic stability was confirmed in six healthy male subjects who received a single 300?mg oral dose of [¹⁴C]-omadacycline (36.6 μCi). Absorption was rapid with peak radioactivity (～610 ngEq/mL) between 1–4?h in plasma or blood. The AUC_last of plasma radioactivity (only quantifiable to 8?h due to low radioactivity) was 3096 ngEq?h/mL and apparent terminal half-life was 11.1?h. Unchanged omadacycline reached peak plasma concentrations (～563?ng/mL) between 1–4?h. Apparent plasma half-life was 17.6?h with biphasic elimination. Plasma exposure (AUC_inf) averaged 9418?ng?h/mL, with high clearance (CL/F, 32.8?L/h) and volume of distribution (Vz/F 828?L). No plasma metabolites were observed.

4.?Radioactivity recovery of the administered dose in excreta was complete (>95%); renal and fecal elimination were 14.4% and 81.1%, respectively. No metabolites were observed in urine or feces, only the omadacycline C4-epimer.     

Pharmacokinetics and disposition of dalcetrapib in rats and monkeys

Abstract

1.?The pharmacokinetics and metabolism of dalcetrapib (JTT-705/RO4607381), a novel cholesteryl ester transfer protein inhibitor, were investigated in rats and monkeys.

2.?In in vitro stability studies, dalcetrapib was extremely unstable in plasma, liver S9 and small intestinal mucosa, and the pharmacologically active form (dalcetrapib thiol) was detected as major component. Most of the active form in plasma was covalently bound to plasma proteins via mixed disulfide bond formation.

3.?Following oral administration of ¹⁴C-dalcetrapib to rats and monkeys, active form was detected in plasma. The active form was mainly metabolized to the glucuronide conjugate and the methyl conjugate at the thiol group. Several minor metabolites including mono- and di-oxidized forms of the glucuronide are also detected in the plasma and urine.

4.?The administered radioactivity was widely distributed to all tissues and mainly excreted into the feces (85.7 and 62.7% of the dose in rats and monkeys, respectively). Most of the radioactivity was recovered by 168?h. Although the absorbed dalcetrapib was hydrolyzed to the active form and was bound to endogenous thiol via formation of disulfide bond, it was relatively rapidly eliminated from the body and was not retained.     

The absorption,distribution and excretion of [14C]lormetazepam in dogs,rabbits, rats and rhesus monkeys

1. Oral doses of [¹⁴C]lormetazepam (0.05–0.25mg/kg) were rapidly and almost completely absorbed by female dogs, rabbits, rats and rhesus monkeys. Elimination of ¹⁴C was rapid and similar after oral or i.v. doses.

2. Rats excreted most of the dose in the faeces (76%), whereas dogs, rabbits and monkeys excreted it in the urine (60, 85 and 80% respectively. The urinary excretion half-lives of ¹⁴C from monkeys (c. 10?h), rabbits (c. 12?h), dogs (c. 14?h) and rats (c. 8?h) paralleled the rate of decline of plasma concn. of ¹⁴C.

3. Biliary excretion of lormetazepam and/or its metabolites occurred in rats (83%), dogs (48%) and possibly to a lesser extent in the other two species. Enterohepatic circulation of ¹⁴C in rat was extensive (47%), but not of long duration, and probably occurred in dog and rabbit.

4. Mean peak plasma concn. of ¹⁴C in dogs, rabbits, rats and monkeys of 190, 29, 42 and 280 ng equiv./ml respectively were reached at 1.5, 1, 0.5 and 1?h. A.U.C. values after oral and i.v. doses were similar in dogs, rats and monkeys. In these species, plasma concn. declined biphasically with t_1/2 values of about 15, 14 and 11?h respectively.

5. Concn. of ¹⁴C in rat tissues, particularly in blood cells, liver, kidneys and gut, were several times greater than those in plasma after single or multiple oral doses. Some accumulation in tissues occurred after multiple doses, presumably partly because of accumulation of ¹⁴C in blood cells.

6. Transplacental transfer of ¹⁴C into foetuses of rats or rabbits was low. In rabbits, maternal: foetal concn. ratios ranged between 9 and 26 : 1 after oral or i.v. doses.

7. The excretion (rats and dogs), or plasma ¹⁴C concn.-time profiles (dogs), were not altered during multiple oral doses for 21 days.     

Absorption,distribution and excretion of nilvadipine,a new dihydropyridine calcium antagonist,in rats and dogs

1. The absorption, distribution and excretion of nilvadipine have been studied in male rats and dogs after an i.v. (1 mg/kg for rats, 0.1 mg/kg for dogs) and oral dose (10 mg/kg for rats, 1 mg/kg for dogs) of ¹⁴C-nilvadipine.

2. Nilvadipine was rapidly and almost completely absorbed after oral dosing in both species; oral bioavailability was 4.3% in rats and 37.0% in dogs due to extensive first-pass metabolism. The ratios of unchanged drug to radioactivity in plasma after oral dosing were 0.4–3.5% in rats and 10.4–22.6% in dogs. The half-lives of radioactivity in plasma after i.v. and oral dosing were similar, i.e. 8–10h in rats, estimated from 2 to 24 h after dosing and 1.5 d in dogs, estimated from 1 to 3 d. In contrast, plasma concentrations of unchanged drug after i.v. dosing declined biexponentially with terminal phase half-lives of 1.2 h in rats and 4.4 h in dogs.

3. After i.v. dosing to rats, radioactivity was rapidly distributed to various tissues, and maintained in high concentrations in the liver and kidneys. In contrast, after oral dosing to rats, radioactivity was distributed mainly in liver and kidneys.

4. With both routes of dosing, urinary excretion of radioactivity was 21–24% dose in rats and 56–61% in dogs, mainly in 24 h. After i.v. dosing to bile duct-cannulated rats, 75% of the radioactive dose was excreted in the bile. Only traces of unchanged drug were excreted in urine and bile.     

Absorption,distribution, metabolism and excretion of the novel SARM GTx-024 [(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide] in rats

Abstract

1. GTx-024, a novel selective androgen receptor modulator, is currently being investigated as an oral treatment for muscle wasting disorders associated with cancer and other chronic conditions.

2. Absorption of GTx-024 was rapid and complete, with high oral bioavailability. A wide tissue distribution of [¹⁴C]GTx-024 derived radioactivity was observed. [¹⁴C]GTx-024-derived radioactivity had a moderate plasma clearance (117.7 and 74.5?mL/h/kg) and mean elimination half-life of 0.6?h and 16.4?h in male and female rats, respectively.

3. Fecal excretion was the predominant route of elimination, with ～70% of total radioactivity recovered in feces and 21–25% in urine within 48?h. Feces of intact rats contained primarily unchanged [¹⁴C]GTx-024 (49.3–64.6%). Metabolites were identified in urine and feces resulting from oxidation of the cyanophenol ring (M8, 17.6%), hydrolysis and/or further conjugation of the amide moiety (M3, 8–12%) and the cyanophenol ring (M4, 1.3–1.5%), and glucuronidation of [¹⁴C]GTx-024 at the tertiary alcohol (M6, 3.5–3.7%). There was no quantifiable metabolite in plasma.

4. In summary, in the rat GTx-024 is completely absorbed, widely distributed, biotransformed through several metabolic pathways, and eliminated in feces primarily as an unchanged drug.     

Pharmacokinetics and metabolite profiling of fimasartan,a novel antihypertensive agent,in rats

Abstract

1.?The objectives of this study were to evaluate the pharmacokinetics and metabolism of fimasartan in rats.

2.?Unlabeled fimasartan or radiolabeled [¹⁴C]fimasartan was dosed by intravenous injection or oral administration to rats. Concentrations of unlabeled fimasartan in the biological samples were determined by a validated LC/MS/MS assay. Total radioactivity was quantified by liquid scintillation counting and the radioactivity associated with the metabolites was analyzed by using the radiochemical detector. Metabolite identification was conducted by product ion scanning using LC/MS/MS.

3.?After oral administration of [¹⁴C]fimasartan, total radioactivity was found primarily in feces. In bile duct cannulated rats, 58.8?±?14.4% of the radioactive dose was excreted via bile after oral dosing. Major metabolites of fimasartan including the active metabolite, desulfo-fimasartan, were identified, yet none represented more than 7.2% of the exposure of the parent drug. Fimasartan was rapidly and extensively absorbed and had an oral bioavailability of 32.7–49.6% in rats. Fimasartan plasma concentrations showed a multi-exponential decline after oral administration. Double peaks and extended terminal half-life were observed, which was likely caused by enterohepatic recirculation.

4.?These results provide better understanding on the pharmacokinetics of fimasartan and may aid further development of fimasartan analogs.     

Pharmacokinetics,metabolism and excretion of an inhibitor of inducible nitric oxide synthase,L-NIL-TA,in dog

1.?The pharmacokinetics, metabolism and excretion of L-NIL-TA, an inducible nitric oxide synthase inhibitor, were investigated in dog.

2.?The dose of [¹⁴C]L-NIL-TA was rapidly absorbed and distributed after oral and intravenous administration (5?mg?kg^?1), with C_max of radioactivity of 6.45–7.07?μg equivalents?g^?1 occurring at 0.33–0.39-h after dosing. After oral and intravenous administration, radioactivity levels in plasma then declined with a half-life of 63.1 and 80.6-h, respectively.

3.?Seven days after oral and intravenous administrations, 46.4 and 51.5% of the radioactive dose were recovered in urine, 4.59 and 2.75% were recovered in faeces, and 22.4 and 22.4% were recovered in expired air, respectively. The large percentages of radioactive dose recovered in urine and expired air indicate that [¹⁴C]L-NIL-TA was well absorbed in dogs and the radioactive dose was cleared mainly through renal elimination. The mean total recovery of radioactivity over 7 days was approximately 80%.

4.?Biotransformation of L-NIL-TA occurred primarily by hydrolysis of the 5-aminotetrazole group to form the active drug L-N6-(1-iminoethyl)lysine (NIL or M3), which was further oxidized to the 2-keto acid (M5), the 2-hydroxyl acid (M1), an unidentified metabolite (M2) and carbon dioxide. The major excreted products in urine were M1 and M2, representing 22.2 and 21.2% of the dose, respectively.