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,distribution, and disposition of esaxerenone,a novel,highly potent and selective non-steroidal mineralocorticoid receptor antagonist,in rats and monkeys

1.?Esaxerenone (CS-3150) is a novel non-steroidal mineralocorticoid receptor antagonist. The pharmacokinetics, tissue distribution, excretion, and metabolism of esaxerenone were evaluated in rats and monkeys.

2.?Following intravenous dosing of esaxerenone at 0.1–3?mg/kg, the total body clearance and the volume of distribution were 3.53–6.69?mL/min/kg and 1.47–2.49?L/kg, respectively, in rats, and 2.79–3.69?mL/min/kg and 1.34–1.54?L/kg, respectively, in monkeys. The absolute oral bioavailability was 61.0–127% in rats and 63.7–73.8% in monkeys.

3.?After oral administration of [¹⁴C]esaxerenone, the radioactivity was distributed widely to tissues, with the exception of a low distribution to the central nervous system. Both in rats and in monkeys, following oral administration of [¹⁴C]esaxerenone the main excretion route of the radioactivity was feces.

4.?Five initial metabolic pathways in rats and monkeys were proposed to be N-dealkylation, carboxylation, hydroxymethylation, O-glucuronidation, and O-sulfation. The oxidized metabolism was predominant in rats, while both oxidation and glucuronidation were predominant in monkeys.     

Pharmacokinetic characterization of hydroxylpropyl-β-cyclodextrin-included complex of cryptotanshinone,an investigational cardiovascular drug purified from Danshen (Salvia miltiorrhiza)

1.?The study aimed to investigate the pharmacokinetics of cryptotanshinone in a hydroxylpropyl-β-cyclodextrin-included complex in dogs and rats.

2.?Animals were administrated the inclusion complex of cryptotanshinone and the concentrations of cryptotanshinone and its major metabolite tanshinone IIA were determined by a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method.

3.?Cryptotanshinone in inclusion complex was absorbed slowly after an oral dose, and the C_max and AUC_0–t were dose-proportional. The bioavailability of cryptotanshinone in rats was (6.9%?±?1.9%) at 60 mg kg^?1and (11.1%?±?1.8%) in dogs at 53.4 mg kg^?1. The t_1/2 of the compound in rats and dogs was 5.3–7.4 and 6.0–10.0 h, respectively. Cryptotanshinone showed a high accumulation in the intestine, lung and liver after oral administration, while the lung, liver and heart had the highest level following intravenous dose. Excretion data in rats showed that cryptotanshinone and its metabolites were mainly eliminated from faeces and bile, and the dose recovery rate was 0.02, 2.2, and 14.9% in urine, bile, and faeces, respectively.

4.?The disposition of cryptotanshinone in an inclusion complex was dose-independent and the bioavailability was increased compared with that without cyclodextrin used to formulate the drug. Cryptotanshinone was distributed extensively into different organs. Excretion of cryptotanshinone and its metabolites into urine was extremely low, and they were mainly excreted into faeces and bile.     

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.     

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.     

Investigation of the influence of glycyrrhizin on the pharmacokinetics of celastrol in rats using LC-MS and its potential mechanism

1.?The aim of this study was to investigate the effects of glycyrrhizin on the pharmacokinetics of celastrol in rats.

2.?Twelve male Sprague–Dawley rats were randomly assigned to two groups: control group and test group. Test group was pretreated with glycyrrhizin at a dose of 100?mg/kg/day for 10 days, and then the two groups were orally administered with celastrol at a dose of 1?mg/kg. The concentration of celastrol was determined using a sensitive and reliable LC-MS method.

3.?The results showed that glycyrrhizin could significantly decrease the plasma concentration (from 64.36?ng/mL to 38.42?ng/mL) and AUC_0?t (from 705.39 to 403.43?μg·h/L) of celastrol in rats. To investigate its potential mechanism, the effects of glycyrrhizin on the transport and metabolic stability of celastrol were investigated using Caco-2 cell monolayer transwell model and rat liver microsome incubation systems. The Caco-2 cell monolayer transwell experiments indicated that glycyrrhizin could increase the efflux ratio of celastrol (4.02 versus 6.51). However, the rat liver microsome incubation experiments showed that glycyrrhizin could significantly increase the intrinsic clearance rate of celastrol from 20.3?±?3.37 to 38.8?±?4.18?μL/min/mg protein.

4.?In conclusion, these results indicated that the herb–drug interaction between glycyrrhizin and celastrol might occur when they were coadministered.     

Pharmacokinetics of chlorogenic acid and corydaline in DA-9701, a new botanical gastroprokinetic agent,in rats

Abstract

1.?Few studies describing the pharmacokinetic properties of chlorogenic acid (CA) and corydaline (CRD) which are marker compounds of a new prokinetic botanical agent, DA-9701, have been reported. The aim of the present study is to evaluate the pharmacokinetic properties CA and CRD following intravenous and oral administration of pure CA (1–8?mg/kg) or CRD (1.1–4.5?mg/kg) and their equivalent dose of DA-9701 to rats.

2.?Dose-proportional AUC and dose-independent clearance (10.3–12.1?ml/min/kg) of CA were observed following its administration. Oral administration of CA as DA-9701 did not influence the oral pharmacokinetic parameters of CA. Incomplete absorption of CA, its decomposition in the gastrointestinal tract, and/or pre-systemic metabolism resulted in extremely low oral bioavailability (F) of CA (0.478–0.899%).

3.?CRD showed greater dose-normalized AUC in the higher dose group than that in lower dose group(s) after its administration due to saturation of its metabolism via decreased non-renal clearance (by 51.3%) and first-pass extraction. As a result, the F of CRD following 4.5?mg/kg oral CRD (21.1%) was considerably greater than those of the lower dose groups (9.10 and 13.8%). However, oral administration of CRD as DA-9701 showed linear pharmacokinetics as a result of increased AUC and F in lower-dose groups (by 182% and 78.5%, respectively) compared to those of pure CRD. The greater oral AUC of CRD for DA-9701 than for pure CRD could be due to decreased hepatic and/or GI first-pass extraction of CRD by other components in DA-9701.     

Pharmacokinetic interaction of entinostat and lapatinib following single and co-oral administration in rats

Abstract

1.?Entinostat, also known as SNDX-275 or MS-275, is a novel, potent, orally bioavailable, class I selective histone deacetylase inhibitor. Pre-clinical data has show that MS-275 can enhance the activity of lapatinib in HER²⁺ metastatic inflammatory and non-inflammatory breast cancer. This study examined whether oral administration of MS-275 to the rats with lapatinib led to any pharmacokinetic interactions.

2.?To evaluate pharmacokinetic interaction of MS-275 and lapatinib in rat, a sensitive and simple LC-MS method was developed to simultaneously determine MS-275 and lapatinib in rat plasma with carbamazepine as internal standard (IS). Eighteen rats were divided randomly into three groups, lapatinib group (lapatinib 15?mg/kg, n?=?8), MS-275 group (MS-275 15?mg/kg, n?=?8) and co-administration group (MS-275 15?mg/kg and lapatinib 15?mg/kg, n?=?8).

3.?There was no statistical pharmacokinetics difference for MS-275 in MS-275 group and co-administration group; the lapatinib could not influence the pharmacokinetic profile of MS-275 in rats. However, there is a statistical pharmacokinetics difference between lapatinib in the lapatinib group and co-administration group, when co-oral administration MS-275 with lapatinib, AUC increased from 2375.5 to 9900.3?ng/mL h (p?<?0.05), C_max increased from 538.0 to 2578.2?ng/mL (p?<?0.01), CL decreased from 6.2 to 1.7?L/h/kg (p?<?0.01).

4.?These data indicate MS-275 could obviously influence the pharmacokinetic profile of lapatinib in rats, which might cause drug–drug interactions in humans when using lapatinib with MS-275. Further investigations should be carried out to elucidate the synergistic mechanisms between the two drugs.     

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).     

Pharmacokinetics,dose proportionality and permeability of S002-333 and its enantiomers,a potent antithrombotic agent,in rabbits

Abstract

1.?S002-333 [(2-(4′-methoxy-benzenesulfonyl)-2,3,4,9-tetrahydro-1H-pyrido (3,4-b) indole-3-carboxylic acid amide)] is a novel and potent antithrombotic active agent. The present work investigates the pharmacokinetics, bioavailability, dose proportionality and permeability of the racemate, S002-333 in male New Zealand White (NZW) rabbits.

2.?Rabbits were administered single intravenous (i.v.) (2?mg/kg) and three oral doses of 10, 20 and 40?mg/kg of S002-333, respectively, at different occasions to evaluate dose proportionality. Serial blood samples were collected and analyzed by a liquid chromatography tandem mass spectrometry (LC-MS/MS) method. Since S002-333 is a racemate consisting of S004-1032 (R) and S007-1558 (S), same samples were analyzed using a chiralcel column so as to evaluate the respective enantiomers.

3.?The peak plasma concentration, after oral administration, occurred at ～10?h post-dose. The clearance (CL) and volume of distribution (V_d) after i.v. dose were found to be 3.05?±?0.09?l/h/kg and 6.73?±?1.16?l/kg, respectively. The absolute oral bioavailability of S002-333 was 16.32%, whereas it was 6.62 and 5.90% for R- and S-enantiomers, respectively. The absolute bioavailability of 10, 20 and 40?mg/kg doses were found to be 27.91, 14.39 and 16.91%, respectively. The PAMPA (parallel artificial membrane permeability assay) assay shows that S002-333 has a low-passive permeability at gastric and intestinal environment.

4.?In conclusion, S002-333 has low-passive permeability, low CL and large V_d. The R-enantiomer has a “slightly” greater bioavailability than the S-enantiomer.     

The effect of resveratrol on pharmacokinetics of aripiprazole in vivo and in vitro

1.?The objective of this study were to investigate the effect of orally administered resveratrol on the pharmacokinetics of aripiprazole (APZ) in rat, and the inhibitory effects of resveratrol on APZ dehydrogenation activity in liver microsomes and human cytochrome P450 3A4 and 2D6.

2.?Twenty-five healthy male Sprague–Dawley rats were randomly divided into five groups: A (control group), B (multiple dose of 200?mg/kg resveratrol), C (multiple dose of 100?mg/kg resveratrol), D (a single dose of 200?mg/kg resveratrol) and E (a single dose of 100?mg/kg resveratrol). A single dose of 3?mg/kg APZ administered orally 30?min after administration of resveratrol. In addition, CYP2D6*1, CYP3A4*1, human and rat liver microsomes were performed to determine the effect of resveratrol on the metabolism of APZ in vitro.

3.?The multiple dose of 200 or 100?mg/kg resveratrol significantly increased the AUC and C_max of APZ. The resveratrol also obviously decreased the CL, but without any significant difference on t_1/2 in vivo. On the other hand, resveratrol showed inhibitory effect on CYP3A4*1, CYP2D6*1, human and rat microsomes, the IC₅₀ of resveratrol was 6.771, 87.87, 45.11 and 35.59?μmol?l^?1, respectively.

4.?Those results indicated more attention should be paid when APZ was administrated combined with resveratrol.     

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.     

Investigation on pharmacokinetics,tissue distribution and excretion of a novel platinum anticancer agent in rats by Inductively Coupled Plasma Mass Spectrometry (ICP-MS)

Abstract

1.?DN604 is a new platinum agent with encouraging anticancer activity. The present study was to explore the pharmacokinetic profiles, distribution and excretion of platinum in Sprague–Dawley rats after intravenous administration of DN604. A sensitive and selective inductively coupled plasma mass spectrometry (ICP-MS) method was established for determination of platinum in biological specimens. The pharmacokinetic parameters were calculated by a non-compartmental method.

2.?The area under concentration–time curve AUC_0?t and AUC_0?∞ for platinum originating from DN604 at 10?mg/kg were 25.15?±?1.29 and 28.72?±?1.04?μg/hml, respectively. The mean residence time MRT was 36.59?±?6.65?h. The volume of distribution V_z was 11.42?±?2.49?l/kg and clearance CL was 0.18?±?0.01?l/h/kg. In addition, the elimination half-life T_1/2z was 44.83?±?9.75?h. After intravenous administration of DN604, platinum was extensively distributed in most of tested tissues except brain. The majority of platinum excreted via urine, and its accumulative excretion ratio during the period of 120?h was 63.5%?±?7.7% for urine, but only 6.94%?±?0.11% for feces.

3.?The satisfactory half-life, wide distribution and high excretion made this novel platinum agent worthy of further research and development.     

Leishmanicidal candidate LASSBio-1736, a cysteine protease inhibitor with favorable pharmacokinetics: low clearance and good distribution

Abstract

1.?LASSBio-1736 ((E)-1-4(trifluoromethyl) benzylidene)-5-(2-4-dichlorozoyl) carbonylhydrazine) is proposed to be an oral cysteine protease leishmanicidal inhibitor.

2.?This work aimed to investigate plasma pharmacokinetics, protein binding and tissue distribution of LASSBio-1736 in male Wistar rats.

3.?LASSBio-1736 was administered to male Wistar rats at doses of 3.2?mg/kg intravenously and 12.6?mg/kg oral and intraperitoneal. The individual plasma-concentration profiles were determined by HPLC-UV and evaluated by non-compartmental and population pharmacokinetic analysis (Monolix 2016R1, Lixoft). Tissue distribution was evaluated after iv injection of 3.2?mg/kg drug by non-compartmental approach.

4.?After intravenous administration, Vd_ss (1.79?L/kg), t _½ (23.1?h) and CL_tot (56.1?mL/h/kg) were determined, and they were statistically similar (α?=0.05) to oral and intraperitoneal pharmacokinetic parameters. The plasma profiles obtained after intravenous, oral and intraperitoneal administration of the compound were best fitted to a three-compartment and one-compartment open model with first-order absorption.

5.?The intraperitoneal and oral bioavailability were around 40 and 15%, respectively.

6.?Liver, spleen and skin tissues showed penetration of 340, 130 and 40%, respectively, with t _½ like plasma values.

7.?LASSBio-1736 protein binding was 95?±?2%.

8.?The t _½, CL_tot and tissue distribution of the compound agreed with the desired drug characteristics for leishmanicidal activity.     

The biological fate of decabromodiphenyl ethane following oral,dermal or intravenous administration

1.?It was important to investigate the disposition of decabromodiphenyl ethane (DBDPE) based on concerns over its structural similarities to decabromodiphenyl ether (decaBDE), high potential for environmental persistence and bioaccumulation, and high production volume.

2.?In the present study, female Sprague Dawley rats were administered a single dose of [¹⁴C]-DBDPE by oral, topical or IV routes. Another set of rats were administered 10 daily oral doses of [¹⁴C]-DBDPE. Male B6C3F1/Tac mice were administered a single oral dose.

3.?DBDPE was poorly absorbed following oral dosing, with 95% of administered [¹⁴C]-radioactivity recovered in the feces unchanged, 1% recovered in the urine and less than 3% in the tissues at 72?h. DBDPE excretion was similar in male mice and female rats. Accumulation of [¹⁴C]-DBDPE was observed in liver and the adrenal gland after 10 daily oral doses to rats.

4.?Rat and human skin were used to assess potential dermal uptake of DBDPE. The dermis was a depot for dermally applied DBDPE; conservative estimates predict ～14?±?8% of DBDPE may be absorbed into human skin in vivo; ～7?±?4% of the parent chemical is expected to reach systemic circulation following continuous exposure (24?h).

5.?Following intravenous administration, ～70% of the dose remained in tissues after 72?h, with the highest concentrations found in lung (1223?±?723?pmol-eq/g), spleen (1096?±?369?pmol-eq/g) and liver (366?±?98?pmol-eq/g); 5?±?1% of the dose was recovered in urine and 26?±?4% in the feces.     

The pharmacokinetics and disposition of MK-0524, a Prostaglandin D2 receptor 1 antagonist,in rats,dogs and monkeys

MK-0524 is a potent, selective and orally active Prostaglandin D₂ receptor 1 (DP₁) antagonist currently under clinical development for the treatment of niacin-induced flushing. Experiments to study the pharmacokinetics, metabolism and excretion of MK-0524 were conducted in rats, dogs and monkeys. MK-0524 displayed linear kinetics and rapid absorption following an oral dose. Following intravenous (i.v.) administration of MK-0524 to rats and dogs (1 and 5?mg/kg), the mean Cl_p was ～2 and ～6?ml/min/kg, the T_1/2 was ～7 and ～13?h and the Vd_ss was ～1 and ～5 L/kg, respectively. In monkeys dosed i.v. at 3?mg/kg, the corresponding values were 8?ml/min/kg, 3?h and 1?L/kg, respectively. Following oral dosing of MK-0524 to rats (5, 25 and 100?mg/kg), dogs (5?mg/kg) and monkeys (3?mg/kg), the absorption was rapid with the mean C_max occurring between 1 and 4?h. Absolute oral bioavailability values in rats, dogs and monkeys were 50, 70 and 8%, respectively. The major circulating metabolite was the acyl glucuronide of MK-0524 (M2), with ratios of glucuronide to the parent aglycone being highest in the monkey followed by dog and rat. In bile duct-cannulated rats and dogs, MK-0524 was eliminated primarily via acyl glucuronidation followed by biliary excretion of the acyl glucuronide, M2, the major drug-related entity in bile.     

Some pharmacokinetic parameters of salvianolic acid A following single-dose oral administration to rats

Context: Salvianolic acid A (Sal A) is a hydrophilic bioactive compound isolated from Salvia miltiorrhiza Bunge (Lamiaceae). It exerts beneficial effects after oral administration on diabetic complications.

Objective: To systematically study the absorption, distribution and excretion of Sal A after single-dose oral administration.

Materials and methods: Animal experiments were conducted in Sprague-Dawley rats. Plasma was sampled at designated times after oral doses of 5, 10 and 20?mg/kg, and an intravenous dose of 50?μg/kg. Tissues were harvested at 10, 60 and 120?min postdosing. Bile, urine and feces were collected at specified intervals before and after dosing. Absorption and distribution characteristics were analyzed by LC–MS, and excretion characteristics were analyzed by UPLC–MS/MS. The Caco-2 cell model was applied to investigate potential mechanisms.

Results: The C_max (5?mg/kg: 31.53?μg/L; 10?mg/kg: 57.39?μg/L; 20?mg/kg: 111.91?μg/L) of Sal A increased linearly with doses (r> 0.99). The calculated absolute bioavailability was 0.39–0.52%. Transport experiment showed poor permeability and the ratio of P_B–A to P_A–B was 3.13–3.97. The highest concentration of Sal A was achieved in stomach followed by small intestine and liver, and it could also be detected in brain homogenate. Approximately 0.775% of its administered dose was excreted via feces, followed by bile (0.00373%) and urine (0.00252%).

Discussion and conclusions: These results support the future development of Sal A as an oral drug for the treatment of diabetic complications. Future research should be conducted to investigate the reason for its poor bioavailability and improve this situation.     

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.     

The metabolism and pharmacokinetics of [14C]-S-777469, a new cannabinoid receptor 2 selective agonist,in healthy human subjects

Abstract

1.?The metabolism and pharmacokinetics of S-777469 were investigated after a single oral administration of [¹⁴C]-S-777469 to healthy human subjects.

2.?Total radioactivity was rapidly and well absorbed in humans, with C_max of 11?308?ng eq. of S-777469/ml at 4.0?h. The AUC_inf ratio of unchanged S-777469 to total radioactivity was approximately 30%, indicating that S-777469 was extensively metabolized in humans.

3.?The metabolite profiling in human plasma showed that S-777469 5-carboxymethyl (5-CA) and S-777469 5-hydroxymethyl (5-HM) were the main circulating metabolites, and the AUC_inf ratio of 5-CA and 5-HM to total radioactivity were 24 and 9.1%, respectively. These data suggest that S-777469 was subsequently metabolized to 5-CA in humans although the production amount of 5-CA was extremely low in human hepatocytes.

4.?Total radioactivity was mainly excreted via the feces, with 5-CA and 5-HM being the main excretory metabolites in feces and urine. Urinary excretion of 5-CA was comparable with that of 5-HM, whereas fecal excretion of 5-CA was lower than that of 5-HM.

5.?In conclusion, the current mass balance study revealed the metabolic and pharmacokinetic properties of S-777469 in humans. These data should be useful to judge whether or not the safety testing of metabolite of S-777469 is necessary.     

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.