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The pharmacokinetics, metabolism, excretion, mass balance, and tissue distribution of [14C]aficamten were evaluated following oral administration of an 8 mg/kg dose in Sprague Dawley rats and in a quantitative whole-body autoradiography study in Long Evans rats. [14C]Aficamten accounted for ∼80% and a hydroxylated metabolite (M1) accounted for ∼12% of total radioactivity in plasma over 48-h (AUC0–48). Plasma tmax was 4-h and the t1/2 of total plasma radioactivity was 5.8-h. Tissues showing highest Cmax exposures were myocardium and semitendinosus muscle. Most [14C]aficamten-derived radioactivity was excreted within 48-h post-administration. Mean cumulative recovery in urine and faeces over 168-h was 8.3% and 90.7%, respectively. In urine and bile, unchanged aficamten was detected at <0.1 and <0.2% of dose, respectively; however, based on total radioactivity excreted in urine (8.0%) and bile (51.7%), approximately 60% of dose was absorbed. [14C]Aficamten was metabolised by hydroxylation with subsequent glucuronidation where the most abundant metabolite recovered in bile was M5 (35.2%), the oxygen-linked glucuronide of hydroxylated aficamten (M1a). The major metabolite detected in faeces was a 1,2,4-oxadiazole moiety ring-cleaved metabolite (M18, 35.3%), shown to be formed from the metabolism of M5 in incubations with rat intestinal contents solution. [ABSTRACT FROM AUTHOR]

Antibody-drug conjugates (ADCs) are a class of biopharmaceuticals that combine the specificity of monoclonal antibodies (mAbs) with the cytotoxicity of small molecule drugs. 15 ADCs have been approved by regulatory authorities up to now, mainly for indications in oncology, however, this review paper will only focus on the 13 ADCs that have been approved by either the FDA or EMA. ADME (Absorption, Distribution, Metabolism, and Excretion) studies are essential for the development of small molecule drugs to evaluate their disposition properties. These studies help to select drug candidates, determine the optimal dosing regimen and help to identify potential safety concerns for the drug of interest in human. Tissue distribution studies are also important as they facilitate the understanding of the efficacy and safety for parent drug and its metabolites in preclinical and clinical studies. For biologics, ADME studies are usually not required. In this paper, we review the existing approval packages and literature for approved ADCs to determine the extent of ADME studies performed as part of ADC registration packages. We conclude that ADME studies are recommended for the development of ADCs if new linkers and payloads are used that have never been used in humans before as these studies provide valuable information on the pharmacokinetic properties, optimal dosing regimen, and potential safety concerns. However, for the development of ADCs with established linker payload combinations, radiolabelled ADME studies may not be necessary if the distribution, metabolism and excretion properties have been described before. Clinical radiolabelled ADME studies are not recommended where patients are treated for life threating diseases like for indications in oncology. [ABSTRACT FROM AUTHOR]

Artificial Intelligence (AI) is poised or has already begun to influence absorption, distribution, metabolism and excretion (ADME) science. It is not in the area expected – that of superior modelling of ADME data to increase its predictive power. It is influencing traditional exhaustive and careful literature research by providing almost perfect summaries of existing information. This will highly influence how people study, graduate and progress in the ADME sciences. The literature contains many flaws (protein binding influence on unbound drug concentration is one of the examples cited) and without direction AI may help to popularise them. ADME science has a relatively small number of key assays and values, but these are produced under widely varying conditions so large data sets, the best substrate for artificial intelligence, are not readily available to produce new more predictive systems. The use of AI to enrich the databases may be a near term goal. AI is already contributing in other areas such as technical skill assimilation, maintenance of complex instruments (combined with virtual reality) and the processing of pharmacovigilance. [ABSTRACT FROM AUTHOR]

Ethylene glycol 2-ethylhexyl ether (EGEHE) is a solvent used in a variety of applications.We report disposition and metabolism of EGEHE following a single gavage or dermal administration of 50, 150 or 500 mg/kg [14C]EGEHE in rats and mice and in vitro in rat hepatocytes.EGEHE was cleared rapidly in rat hepatocytes (half-life ∼4 min) with no sex difference.EGEHE was well- and moderately absorbed following oral administration (rats: 80-96%, mice: 91-95%) and dermal application (rats: 25-37%, mice: 22-24%), respectively, and rapidly excreted in urine.[14C]EGEHE-derived radioactivity was distributed to tissues (oral: 2.3-7.2%, dermal: 0.7-2.2%) with liver and kidney containing the highest levels in both species.EGEHE was extensively metabolised with little to no parent detected in urine. The alkoxyacetic acid metabolite, which has previously been shown to mediate toxicities of other shorter-chain ethylene glycol ethers, was not detected.There were no apparent dose, species or sex differences in disposition and metabolism of EGEHE, except that the exhaled volatile compounds were greater in mice (19-20%) compared with rats (

1. The current investigation was to develop and validate the LC-MS/MS method in order to analyse the various pharmacokinetic parameters of S019-0385. A sensitive, selective, and robust LC-MS/MS approach was established and validated for measuring S019-0385 in female mice plasma and tissue, using optimal multiple reaction monitoring (MRM) transition m/z 488.25/329.12 on positive mode. On a Waters Symmetry Shield C18 column, the analyte was separated using acetonitrile and deionised water with formic acid within 6 min at 0.7 mL/min. Linearity (R2 ≥ 0.99) was observed across 0.195–100 ng/mL concentration range using linear least-squares regression. 2. Blood-to-plasma ratio and plasma protein drug binding (%) in mice and human was assessed and found to be less than 1 and >83%, respectively. Absolute bioavailability (%F) of S019-0385 in female Swiss mice was exhibited to be 6.90%. Percent dose excreted S019-0385 in unchanged form through urine and faecal was found to be less than 2% and 0.5%, respectively. 3. Following oral administration at 5 mg/kg, the concentration of S019-0385 in tissue distribution was found to be in the order of C small intestine > C bone > C lung > C spleen > C kidney > C liver > C heart > C brain. [ABSTRACT FROM AUTHOR]

Vatiquinone is a potent inhibitor of 15-lipoxygenase and is in clinical development for the treatment of mitochondrial diseases and other disorders characterised by high levels of oxidative stress and dysregulation of energy metabolism. In rats, 14C-vatiquinone-derived radioactivity was quickly and widely distributed throughout the body and cleared from most tissues by 24 h post-dose following a single oral dose of 14C-vatiquinone. Following oral administration, 94% of dose was recovered within seven days in rats, approximately 61% of dose was recovered within seven days in dogs and approximately 93% of dose was recovered within nine days in human subjects (IND 119220). Faecal excretion was the major route (>56% dose) in all species; urinary excretion was minimal in rats and dogs (<3% dose) but was higher in humans (∼ 22% dose). Following oral administration, vatiquinone was the dominant circulating component in rats and dogs but was minor in human subjects. There were no plasma metabolites that were more than 10% of total drug related exposures in all species. Following oral administration, vatiquinone was not detectable in urine but was the most prominent component in faeces in rats, dogs, and humans. [ABSTRACT FROM AUTHOR]

Daridorexant is a dual orexin receptor antagonist developed for the treatment of insomnia disorder and has shown improvement in sleep outcomes and daytime functioning. The present work describes its biotransformation pathways in vitro and in vivo and provides a cross-species comparison between the animal species used in preclinical safety assessments and man. Daridorexant clearance is driven by metabolism along seven distinct pathways. Metabolic profiles were characterised by downstream products while primary metabolic products were of minor importance. The metabolic pattern differed between rodent species, with the rat reflecting the human pattern better than the mouse. In rodents, daridorexant is mostly excreted via the bile after extensive metabolism while urinary excretion was negligible in the rat. Only traces of the parent drug were detected in urine, bile, or faeces. Daridorexant has three major metabolites which are well covered in these preclinical safety species. All of them retain some residual affinity towards orexin receptors. However, none of these is considered to contribute to the pharmacological effect of daridorexant as their active concentrations in the human brain are too low. [ABSTRACT FROM AUTHOR]

SHR0302, a selective JAK1 inhibitor developed by Jiangsu Hengrui Pharmaceutical Co., was intended for the treatment of rheumatoid arthritis. In this study, we evaluated the pharmacokinetics, mass balance, and metabolism of SHR0302 in six healthy Chinese male subjects after a single 8 mg (80 µCi) oral dose of [14C]SHR0302. SHR0302 was absorbed rapidly (Tmax = 0.505 h), and the average t1/2 of the SHR0302-related components in plasma was approximately 9.18 h. After an oral dose was administered, the average cumulative excretion of the radioactive components was 100.56% ± 1.51%, including 60.95% ± 11.62% in urine and 39.61% ± 10.52% in faeces. A total of 16 metabolites were identified. In plasma, the parent drug SHR0302 accounted for 90.42% of the total plasma radioactivity. In urine, SHR161279 was the main metabolite, accounting for 33.61% of the dose, whereas the parent drug SHR0302 only accounted for 5.1% of the dose. In faeces, the parent drug SHR0302 accounted for 23.73% of the dose, and SHR161279 was the significant metabolite, accounting for 5.67% of the dose. In conclusion, SHR0302-related radioactivity was mainly excreted through urine (60.95%) and secondarily through faeces (39.61%). The metabolic reaction of SHR0302 in the human body is mainly through mono-oxidation and glucuronidation. The main metabolic location of SHR0302 in the human body is the pyrrolopyrimidine ring. [ABSTRACT FROM AUTHOR]

Emvododstat is a potent inhibitor of dihydroorotate dehydrogenase and is now in clinical development for the treatment of acute myeloid leukaemia and COVID-19. Following an oral dose administration in Long-Evans rats, 14C-emvododstat-derived radioactivity was widely distributed throughout the body, with the highest distribution in the endocrine, fatty, and secretory tissues and the lowest in central nervous system. Following a single oral dose of 14C-emvododstat in rats, 54.7% of the dose was recovered in faeces while less than 0.4% of dose was recovered in urine 7 days post-dose. Emvododstat was the dominant radioactive component in plasma and faeces. Following a single oral dose of 14C-emvododstat in dogs, 75.2% of the dose was recovered in faeces while 0.5% of dose was recovered in urine 8 days post-dose. Emvododstat was the dominant radioactive component in faeces, while emvododstat and its two metabolites (O-desmethyl emvododstat and emvododstat amide bond hydrolysis product) were the major circulating radioactivity in dog plasma. [ABSTRACT FROM AUTHOR]

1. TP0463518, a novel hypoxia-inducible factor prolyl hydroxylase inhibitor, is reportedly excreted predominantly through urinary excretion in an unchanged form in humans, with partial biliary excretion also possible. However, the clearance mechanisms remain unclear. The aim of this study was to investigate the clearance mechanisms in humans and to assess species differences in the excretion routes. 2. TP0463518 was not metabolised in rat, dog, or human hepatocytes. TP0463518 is a substrate for human BCRP, OATP1B1, OATP1B3, and OAT3, suggesting that renal uptake by OAT3 is probably the predominant clearance route, with hepatic uptake by OATP1B1 and OATP1B3 contributing partially to clearance in humans. 3. A species difference in excretion routes was observed. The unchanged urinary excretion rates in humans, male rats, female rats, dogs, and monkeys were 80.7%, 0.1%, 40.9%, 15.2%, and 72.6%, respectively. Urinary excretion was predominant in humans and monkeys, while only biliary excretion was observed in male rats. Uptake studies using hepatocytes showed that the hepatic uptake clearance in rats was 13.6-fold higher than that in humans. Therefore, not only reabsorption via renal tubules, but also hepatic uptake seems to be involved in the species differences in excretion routes between rats and humans. [ABSTRACT FROM AUTHOR]

Sebetralstat is an investigational oral plasma kallikrein inhibitor for the on-demand treatment of hereditary angioedema. Six healthy male participants received one dose of 600 mg (540 µCi) [14C]-sebetralstat. Plasma concentrations of sebetralstat and levels of total radioactivity in plasma, urine, and faeces were determined. Metabolite profiles of radioactivity were generated, and major metabolites structurally characterised. Radioactivity was rapidly absorbed and was excreted with a mean of 95.8% (63.4% faeces; 32.4% urine) recovered by 216 h. Sebetralstat was the major drug-related component in urine and faeces, although metabolism predominated overall (main metabolites: M19 (des-[methoxy-fluoro-methylpyridine]-sebetralstat), M10 (N-des-pyridone-sebetralstat-carboxylic acid), M3 (pyridine O-desmethyl-sebetralstat), and M34 (pyridine dioxy-dihydro-sebetralstat)). Sebetralstat was the main radiolabelled component in plasma (mean of 64.1% of the total radioactivity AUC0–24), followed by relatively low proportions of metabolites: M19 (7.10%), M3 (4.01%), and M10 (4.00%). Although M19 was >10% of the plasma radioactivity AUC0–24, in one participant it comprised a mean of <10% of AUC0–24. Plasma levels of M19 were measured at the NOAEL dose in a rat toxicology study, where higher exposure was observed vs. that in humans. Given these findings and the lack of pharmacological activity of M19, it was concluded that there was no unique or disproportionate circulating metabolite in humans. [ABSTRACT FROM AUTHOR]

The pharmacokinetics, elimination, and metabolism of fostemsavir (FTR), a prodrug of the HIV-1 attachment inhibitor temsavir (TMR), were investigated in healthy volunteers. FTR was administered with and without ritonavir (RTV), a protease inhibitor previously shown to boost TMR exposures. In vitro studies were also used to identify the enzymes responsible for the metabolism of TMR. Total recovery of the administered dose ranged from 78% to 89%. Approximately 44% to 58% of the dose was excreted in urine, 20%–36% in faeces, and 5% in bile, as TMR and metabolites. RTV had no effect on the recovery of radioactivity in any matrix. Compared to FTR alone, pre-treatment of subjects with RTV increased the exposure of TMR by ∼66% and reduced the exposure of plasma total radioactivity by ∼68%. The major route of TMR elimination was through biotransformation. TMR, M28 (N-dealkylation), and M4 (amide hydrolysis) were the major circulating components in plasma. Pre-treatment with RTV increased the amount of TMR present, decreased the amount of circulating M28, and M4 was unchanged. CYP3A4 metabolism accounted for 21% of the dose, forming multiple oxidative metabolites. This pathway was inhibited by coadministration of RTV. [ABSTRACT FROM AUTHOR]

Metabolism data for MCPA in rat, dog and human shows a single oral dose is quantitatively and rapidly absorbed with evidence of non-linear kinetics at >100 mg/kg bw. The extent of metabolism is low and consistent between rat and human, with substantially higher metabolic conversion in dog. Parent accounts for 50%–67% dose in rat, ∼40% in human and 2%–27% in dog. No dog specific metabolite is apparent. In rat and human, MCPA and metabolites are rapidly eliminated in urine (65%–70% within 24 h) but in dog, excretion is via urine and faeces (20%–30% within 24 h), with renal excretion saturating between 5 and 100 mg/kg bw. The species difference in excretion is reflected in pharmacokinetics. Terminal half-life is similar in rat and human (15–17 h) but higher in dog (47 h). Modelling shows species differences in single dose kinetics profoundly affect systemic exposure following repeat dosing. The difference in renal excretion and systemic exposure of MCPA between dogs and rats has been attributed to species differences in active transporters (OAT1/OAT3). A new in vitro flux study in renal proximal tubules supports this hypothesis with net secretion in rat and human of a similar magnitude but significantly less in dog. [ABSTRACT FROM AUTHOR]

Dipeptidyl peptidase-4 (DPP-4) inhibitor is a class of oral antihyperglycemic agents and therapeutic approach for type 2 diabetes. Cetagliptin is a novel oral and selective DPP-4 inhibitor and developed as a promising candidate for treatment of type 2 diabetes mellitus. This study aimed to evaluate the metabolism and excretion of cetagliptin in Sprague-Dawley (SD) rats, and to detect and identify metabolites of cetagliptin. The SD rats were administered with a single oral dose of 6 mg/kg with approximately 100 µCi of [14C] cetagliptin. The mean total recovery of radioactivity was 90.20% within 168h in SD rats excreta. Cetagliptin was the major radioactive component in SD rats plasma, urine and eliminated primarily by faecal excretion. The recovery of cetagliptin in urine and feces was 25.15% and 13.85% of the dose, respectively. Cetagliptin was well absorbed after oral administration in SD rats based on the total recovery of radioactivity in BDC SD rats bile and urine. Six major metabolites were observed and identified in SD rats, comprising 0.20 to 4.53% of total plasma AUC. These major metabolites were the hydroxylated, N-sulphate and N-carbamoyl glucuronic acid conjugates of the cetagliptin, two metabolites formed by glucuronide of a hydroxylated metabolite. [ABSTRACT FROM AUTHOR]

YY-20394, a highly selective PI3Kδ inhibitor, is under NDA submission for treating follicular lymphoma in China. The absorption, metabolism, and excretion of YY-20394 were evaluated in healthy Chinese male subjects following a single oral dose of 80 mg [14C]YY-20394 (100 µCi). Within 264 h post-dose, 92.1% of the administered dose was recovered, with 58.1% from urine and 34.0% from faeces. YY-20394 was rapidly absorbed in humans, and the peak plasma concentrations occurred at 1.0 h. The absorbed drug fraction was at least 58.1% according to urine recovery. In addition to the parent drug, nine metabolites were identified in plasma, urine, and faeces. Unchanged YY-20394 was the predominant drug-related component in plasma (accounting for 68.4% of the total radioactivity), urine (accounting for 90.0% of the urinary radioactivity) and faeces (accounting for 41.7% of the faecal radioactivity). In humans, the major metabolic sites were the morphine ring and side chains of piperidine rings. The major metabolic pathways involved N-dealkylation, O-dealkylation, glucuronidation and acetylation. Overall, renal elimination played a significant role in the disposition of YY-20394, and the morphine ring and the side chain of the piperidine ring was the predominant metabolic sites. [ABSTRACT FROM AUTHOR]

The disposition of the hepatoselective ACC inhibitor PF-05221304 (Clesacostat) was studied after a single 50-mg oral dose of [14C]-PF-05221304 to healthy human subjects. Mass balance was achieved with 89.9% of the administered dose recovered in urine and faeces, over the 11-day study period. The total administered radioactivity excreted in faeces and urine was 81.7 and 8.2%, respectively. Unchanged PF-05221304 accounted for 35.6% of the radioactive dose in faeces, suggesting ∼64% of the administered dose was absorbed. PF-05221304 was principally metabolised via oxidative and reductive pathways involving: (a) N-dealkylation, (b) isopropyl group monohydroxylation to yield enantiomeric metabolites (M2a and M2b), (c) hydroxylation on the 3-azaspiro[5.5]undecan-8-one moiety to metabolites M5 and 519c, and (d) carbonyl group reduction to enantiomeric alcohol metabolites M3, and M4. Secondary metabolites (521a, 521b, and 533), derived from a combination of oxidation and reduction of the primary metabolites accounted for ∼14.8% of the dose. In plasma, unchanged PF-05221304 represented 96.1% circulating radioactivity. Metabolites M1, M2b, and M2a represented 1.94, 1.76, and 0.18% of circulating radioactivity, respectively. Overall, these data suggest that PF-05221304 is well absorbed in humans and eliminated largely via phase I metabolism. [ABSTRACT FROM AUTHOR]

Sinoacutine is a natural isoquinoline alkaloid isolated from traditional Chinese medicine Stephanina yunnanensis H. S. Lo. Our aim was to study the pharmacokinetic characteristics of sinoacutine, which is essential during the development of new drugs. In this study, an accurate, sensitive, and efficient liquid chromatography (HPLC) method was developed and applied to evaluate the pharmacokinetics, tissue distribution, plasma protein binding rate, and excretion after intravenous injection of sinoacutine in rats. The pharmacokinetic parameters of sinoacutine were accorded with a two-compartment model in rats, and the AUC0–t in female was greater than that in male. Sinoacutine could be detected in heart, liver, spleen, lung, kidney, and brain, and the content in liver and kidney was relatively high. Meanwhile, it had a high plasma protein binding rate of 79.16%. Excretion of sinoacutine through faeces and urine was low, and the average excretion rate was 9.96%. There were gender differences in blood drug concentration, tissue distribution, and excretion significantly (p < 0.05). In summary, this study lays a foundation for elucidating the pharmacokinetic rule of sinoacutine and the data can provide a reliable scientific resource for further research. [ABSTRACT FROM AUTHOR]

TPN729, a novel phosphodiesterase type 5 (PDE5) inhibitor for the treatment of erectile dysfunction (ED), is in phase II clinical trials in China. Previous studies suggested that TPN729 possesses promising therapeutic value. In previous non-radiolabeled rat excretion studies, the recovery of TPN729 and its major metabolites accounted for approximately 8.58% of the administration dose in urine and faeces by 48 h post-dose. To solve this problem and further study the metabolism of TPN729 in rats, we used the radio-isotopic tracing technique for the first time. In this study, the mass balance, tissue distribution, and metabolism of TPN729 were evaluated in rats after a single oral dose of 25 mg/kg [14C]TPN729 (150 μCi/kg). At 168 h post-dose, the mean total radioactivity recovery of the dose was 92.13%. Faeces was the major excretion route, accounting for 74.63% of the dose, and urine excretion accounted for 17.50%. After oral administration of [14C]TPN729, radioactivity was widely distributed in all examined tissues, and a higher radioactivity concentration was observed in the stomach, large intestine, lung, liver, small intestine, and eyes. The concentration of drug-related materials were similar in plasma and blood cells. A total of 51 metabolites were identified in rat plasma, urine, faeces, and bile, and the predominant metabolically susceptible position of TPN729 was the pyrrolidine moiety. The main metabolic pathways were N-dealkylation, oxidation, and dehydrogenation. In summary, we solved the previous problem of low drug recovery, elucidated the major excretion pathway, determined the tissue distribution patterns, and investigated the metabolism of TPN729 in rats by using a radioisotopic tracing technique. [ABSTRACT FROM AUTHOR]

The metabolism and excretion of cetagliptin were investigated in healthy male subjects after a single oral dose of 100mg/50μCi [14C] cetagliptin. The mean concentration-time profile of cetagliptin was similar to that of total radioactivity in plasma after oral administration of [14C] cetagliptin in healthy male subjects. Cetagliptin was rapidly absorbed after oral administration. Unchanged cetagliptin was the most abundant radioactive component in all matrices investigated. Approximately 53.13% of plasma AUC of total radioactivity was accounted for by cetagliptin. Each metabolite plasma AUC was not higher than 2.93% of plasma AUC of total radioactivity. By 336 h after administration, 91.68% of the administered radioactivity was excreted, and the cumulative excretion in the urine and faeces was 72.88% and 18.81%, respectively. The primary route of excretion of radioactivity was via the kidneys. Four metabolites were detected at trace levels, and it involved hydroxylated (M436-1 and M436-3), N- sulphate (M500), and N-carbamoyl glucuronic acid conjugates (M640B) of cetagliptin. These metabolites were detected also in plasma, urine, and faeces at low levels, except that metabolite M640B was not detected in faeces. All metabolites were observed with <10% of parent compound systemic exposure after oral administration. [ABSTRACT FROM AUTHOR]

The disposition of radioactivity following subcutaneous 14C-razuprotafib, a Tie2 activator, was explored in multiple species. The absorption and clearance of razuprotafib and total radioactivity in human plasma are rapid and pharmacokinetics support razuprotafib as primary circulating component. Radioactivity is distributed greater to human plasma than whole blood (B:P = 0.36). In pigmented rats, radioactivity distributes to whole-body tissues rapidly and, within 24 h, is localised to elimination pathway end organs and injection site. Overall recovery of radioactivity across species is >93%, with the majority recovered within 24–48 h, and >80% in faeces. The CYP2C8 enzyme contributes significantly to razuprotafib metabolism. A hydrolysis product of razuprotafib (m/z− 380) is the main component in rat plasma at 2 h (49% peak area radioactivity), while razuprotafib (m/z− 585) is the main component in plasma for dog (58%), monkey (99.3%), and human (100%). Razuprotafib is present in dog, monkey, and human faeces, with the greatest percentage of radioactivity as metabolites. The major metabolite (>25%) in monkey and human, m/z− 633, is an S-methylated oxidised derivative of razuprotafib and is localised in faeces. Overall disposition of 14C-razuprotafib in human is best modelled by monkey over lower order species. [ABSTRACT FROM AUTHOR]

Rhubarb, a famous traditional Chinese medicine, shows a wide range of physiological activities and pharmacological benefits. Rhubarb anthraquinones are perceived as the pharmacologically active compounds of Rhubarb, and understanding metabolism of them is crucial to assure safety and effectiveness of clinical application. In this study, the pharmacokinetics, tissue distribution and excretion of five rhubarb anthraquinones (aloe-emodin, rhein, emodin, chrysophanol, physcion) were systematically investigated after oral administration of rhubarb extract to rats. An HPLC method was developed and validated for quantitation of five rhubarb anthraquinones in rat plasma, tissues, urine and faeces to investigate the Pharmacokinetic characteristics. The results showed that the proposed method was suitable for the quantification of five anthraquinones in plasma, tissue and excreta samples with satisfactory linear (r > 0.99), precision (<10%) and recovery (85.12–104.20%). The plasma concentration profiles showed a quick absorption with the mean Tmax of 0.42–0.75 h and t1/2 of 6.60–15.11 h for five anthraquinones. The analytes were widely distributed in most of the tissues. Approximately 0.13–10.59% and 28.47–81.14% of five anthraquinones were recovered in urine and faeces within 132 h post-dosing, which indicated the major elimination route was faeces excretion. In summary, this study lays a foundation for elucidating the pharmacokinetic rule of rhubarb anthraquinone and the important data can provide reliable scientific resource for further research. [ABSTRACT FROM AUTHOR]

The absorption, metabolism and excretion of pictilisib, a selective small molecule inhibitor of class 1 A phosphoinositide 3-kinase (PI3K), was characterized following a single oral administration of [14C]pictilisib in rats, dogs and humans at the target doses of 30 mg/kg, 5 mg/kg and 60 mg, respectively. Pictilisib was rapidly absorbed with Tmax less than 2 h across species. In systemic circulation, pictilisib represented the predominant total radioactivity greater than 86.6% in all species. Total pictilisib and related radioactivity was recovered from urine and faeces in rats, dogs, and human at 98%, 80% and 95%, respectively, with less than 2% excreted in urine and the rest excreted into faeces. In rat and dog, more than 40% of drug-related radioactivity was excreted into the bile suggesting biliary excretion was the major route of excretion. Unchanged pictilisib was a minor component in rat and dog bile. The major metabolite in bile was O-glucuronide of oxidation on indazole moiety (M20, 21% of the dose) in rats and an oxidative piperazinyl ring-opened metabolite M7 (10.8% of the dose) in dogs. Oxidative glutathione (GSH) conjugates (M18, M19) were novel metabolites detected in rat bile, suggesting the potential generation of reactive intermediates from pictilisib. The structure of M18 was further confirmed by NMR to be a N-hydroxylated and GSH conjugated metabolite on the moiety of the indazole ring. [ABSTRACT FROM AUTHOR]

The metabolism, excretion, and pharmacokinetics of mirogabalin were investigated following a single oral administration of [14C]mirogabalin at 30 mg/5.55 MBq to six healthy male subjects. The mean recovery values of radioactivity in urine and faeces were 96.85 and 1.21%, respectively. The main component of radioactivity in the plasma, urine, and faeces was mirogabalin. A204-4455 (lactam form), mirogabalin N-glucuronide, and glucuronide of oxidized A204-4455 were detected as minor components in the specimens. Renal clearance of mirogabalin was higher than the glomerular filtration rate of the human kidneys, indicating renal secretion is involved in the clearance. In vitro studies revealed that UDP-glucuronosyltransferase produced two metabolites: A204-4455, formed via mirogabalin acylglucuronide, and a ring-opened form of mirogabalin N-glucuronide. Mirogabalin was absorbed almost completely, and was eliminated via urine. A part of the orally administered dose of mirogabalin was metabolized through glucuronidation at the amine and carboxylic acid moiety, which represents the primary metabolic pathway. [ABSTRACT FROM AUTHOR]

Absorption, metabolism, and excretion (AME) of licogliflozin, a sodium-glucose co-transporters (SGLTs) 1 and 2 inhibitor, were studied in male rats, dogs, and healthy male volunteers and reported. Oral absorption of licogliflozin was rapid (tmax < 1 h) with absorption estimated at 87%, 100% and 77% in rats, dogs and humans, respectively. Excretion of licogliflozin-related radioactivity was rapid and nearly complete following oral administration with total radioactivity recovery ranging from 73% in dogs, 92.5% in humans, to 100% in rats. Dose-related radioactivity was excreted in both urine and faeces with urinary excretion playing a slightly more important role in humans (∼56%) than in animal species (∼19–41%). Elimination of licogliflozin was predominantly via metabolism with the majority of the radioactivity dose (∼54–74%) excreted as metabolites across species. The principal biotransformation pathways involved direct glucuronidation and oxidation across all species. In humans, direct glucuronidation to M17 and M27 was the major pathway observed, accounting for ∼38% of the dose in excreta while oxidative metabolism also contributed to >29% of the dose in excreta. Oxidative pathways were predominant in animal species. [ABSTRACT FROM AUTHOR]

Polybrominated diphenyl ethers (PBDEs) levels in environmental matrices have generally declined following their phaseout as flame retardants. The objective of this study was to determine the absorption, distribution, metabolism, and excretion of three persistent PBDEs in laying hens and their transfer into eggs. Laying hens (n = 4 per congener) received a single oral dose of BDE-99, -153, or -209 and eggs and excreta were collected daily for 7 days, then tissues were collected and analysed. Cumulative BDE-209 excretion was 93% of dose, and bioavailability was approximately 17%. Lesser amounts of BDE-99 (41%) and -153 (26%) were excreted with bioavailabilities of 87% and 79%, respectively. Phenolic metabolites were observed in excreta extracts from BDE-99 dosed birds. Cumulative transfers based on bioavailability of BDE-99, -153, and -209 to eggs were 17%, 34%, and 15%, respectively. Egg residues were primarily present in yolk (12.3%, 23.5%, and 2.1% of the total dose for BDE-99, -153, and -209, respectively). Adipose, skin, ova, intestine, and thigh muscle contained the highest levels of radioactive tissue residues. These studies demonstrate movement of PBDE residues into edible tissues and eggs of laying hens. [ABSTRACT FROM AUTHOR]

As a novel long-acting recombinant human insulin analogue, it is necessary to carry out the preclinical research for insulin LysArg. The purpose of this study was to characterise the pharmacokinetic, tissue distribution and excretion of insulin LysArg and provide a reference for its development. Three methods were used to measure the content of insulin LysArg in biological samples after a single subcutaneous administration in rats, including radioassay, radioassay after precipitation with TCA and separation by HPLC. After Subcutaneous administration of recombinant insulin LysArg 1, 2, 4 U/kg in rats, it showed both Cmax and AUC0–t were positively correlated with the dose. In the meanwhile, after a single subcutaneous administration of recombinant insulin LysArg at 2 U/kg in rats, the amount of radioactivity in most organs was highest at 1.5 h and then decreased gradually, no accumulation was found. The highest level of insulin LysArg was observed in the kidney. Like other macromolecules, insulin LysArg was mainly excreted from urine. The study fully illustrated the pharmacokinetic pattern of insulin LysArg, provided valuable informations to support its further development about safety and toxicology. [ABSTRACT FROM AUTHOR]

This article describes in vivo biotransformation and disposition of erdafitinib following single oral dose of 3H-erdafitinib and 14C-erdafitinib to intact and bile duct-cannulated (BC) rats (4 mg/kg), 3H-erdafitinib to intact dogs (0.25 mg/kg), and 14C-erdafitinib to humans (12 mg; NCT02692677). Peak plasma concentrations of total radioactivity were achieved rapidly (Tmax: animals, 1 h; humans, 2–3 h). Recovery of drug-derived radioactivity was significantly slower in humans (87%, 384 h) versus animals (rats: 91–98%, 48 h; dogs: 81%, 72 h). Faeces was the primary route of elimination in intact rats (95%), dogs (76%), and humans (69%); and bile in BC rats (48%). Renal elimination of radioactivity was relatively low in animals (2–12%) versus humans (19%). Unchanged erdafitinib was major component in human excreta (faeces, 17%; urine, 11%) relative to animals. M6 (O-desmethyl) was the major faecal metabolite in humans (24%) and rats (intact, 46%; BC, 11%), and M2 (O-glucuronide of M6) was the prevalent biliary metabolite in rats (14%). In dogs, besides M6, majority of radioactive dose in faeces was composed of multiple minor metabolites. In humans, unchanged erdafitinib was the major circulating entity. O-demethylation of erdafitinib was the major metabolic pathway in humans and animals. [ABSTRACT FROM AUTHOR]

TQ-A3326 has been developed as a new drug by modifying the structure of daclatasvir with deuterium. The pharmacokinetics (PK) of TQ-A3326 in human remains unclear. The aim of the present study was to establish a LC-MS/MS method to investigate preliminarily the PK characteristics of TQ-A3326 and its major metabolites in healthy Chinese volunteers. All volunteers were administrated TQ-A3326 (60 mg). Plasma, feces and urine samples were extracted through protein precipitation. A rapid and sensitive LC-MS/MS method was successfully developed and applied to assess the PK properties of TQ-A3326. The AUC0-t and Cmax were 39516.3 ± 10778.5, 1034.6 ± 452.9 and 71.0 ± 49.5 ng·h·mL−1, and 1411.2 ± 325.4, 52.9 ± 16.4 and 1.8 ± 0.5 ng·mL−1, respectively, for TQ-A3326, M2-D and M4-D. Feces were the predominant route of elimination of TQ-A3326. M2-D was an abundant metabolite in feces and urine, representing 23.72% and 0.24% of the dose, respectively. The measurements of TQ-A3326 and its active metabolites would help to better understand the predominant route of elimination of the prototype drug, and provide meaningful information for further investigation of the bioactive mechanism of TQ-A3326 and its clinical applications. [ABSTRACT FROM AUTHOR]

Triclocarban is a residue-producing antibacterial agent used in a variety of consumer products. These studies investigated the disposition and metabolism of [14C]triclocarban. In male rats following a single gavage administration of 50, 150, and 500 mg/kg, excretion was primarily via feces (feces, 85–86%; urine, 3–6%) with no apparent dose-related effect. In male rats, 29% of the administered dose was excreted in bile suggesting some of the fecal excretion is from the absorbed dose which was excreted to the intestine via bile. The tissue retention of radioactivity was low in male rats (24 h, 3.9%; 72 h, 0.1%). Disposition pattern following gavage administration of 50 mg/kg in female rats and male and female mice were similar to male rats. Plasma elimination half-life of triclocarban in rats following gavage administration was shorter (∼2 h) compared to that based on total radioactivity (≥9 h) which included all products of triclocarban. Absorption following a single dermal application of 1.5 or 3% was low (≤3%) in rodents. Hydroxylated and conjugated metabolites of triclocarban predominated in bile. In hepatocytes, clearance of triclocarban in mouse and human was similar and was faster than in rat. [ABSTRACT FROM AUTHOR]

The specialty amine catalyst 2,2′-dimorpholinodiethyl ether (DMDEE) is a high-production volume chemical used in the production of flexible foam, high-resilient molded foam, and in coatings and adhesives. The disposition and metabolism of [14C]DMDEE (20 or 200 mg/kg) were determined in male ane female rats and mice after oral and intravenous administration and dermal application. In male and female rats, following a single oral administration, [14C]DMDEE was well-absorbed and excreted rapidly and extensively via urine (75–93%) and some in feces (∼4–8%). The total radioactivity in tissues at 24 h and 72 h (males only) following oral administration was 8–10% and ∼4%, respectively, suggesting considerable tissue distribution. A moderate amount of the total tissue radioactivity in kidney and liver were unextractable suggesting covalent binding of [14C]DMDEE-derived products in tissue macromolecules. Absorption following a single dermal application in rats was significant (∼64%) with a similar disposition pattern to oral. The oral and dermal disposition of [14C]DMDEE in male and female mice was similar to rats. Urinary products of DMDEE identified were oxidative metabolism of the morpholine ring. Coadministration of DMDEE with nitrite in rats didn't produce the rodent carcinogen, N-nitrosomorpholine. [ABSTRACT FROM AUTHOR]

The compound 20(S),25-epoxydammarane-3β,12β,24α-triol (24-hydroxy-panaxadiol or 24-OH-PD), isolated from the red Panax ginseng CA Meyer possesses anticancer activity. Our aim was to study the pharmacokinetic characteristics of 24-OH-PD, which is essential for pre-clinical research during the development of new drugs. In this study, a simple and sensitive ultra-performance liquid chromatography-mass spectrometry (LC-MS/MS) method was established and used for studying the pharmacokinetics, in vitro protein binding, tissue distribution, and elimination profiles of 24-OH-PD in rats. 24-OH-PD was characterized by linear pharmacokinetics in the dose range of 2.5–10 mg/kg and had relatively longer half-life (4.82–5.45 h) than the other ginsenosides. It had a wide tissue distribution profile in rats and was primarily distributed in the lung. Within 96 h of intravenous administration, 13.84% of 24-OH-PD was excreted out via feces and 0.02% via urine in its unchanged form. In conclusion, a simple LC-MS/MS method with high sensitivity and selectivity was established for the quantification of 24-OH-PD. [ABSTRACT FROM AUTHOR]

Cenerimod is a sphingosine-1-phosphate 1 receptor modulator under development for treatment of systemic lupus erythematosus. This single-centre, open-label, single-dose study investigated the mass balance and excretion routes and aimed at identifying and quantifying cenerimod metabolites in plasma, urine, and faeces after oral administration of 2 mg/100 μCi (3.7 MBq) of 14C-cenerimod. Total mean cumulative recovery was 84% of the administered dose (58–100% in faeces and 4.6–12% in urine). In a 0–504 h cross-subject area under the curve plasma pool, cenerimod and two metabolites were detected accounting for 78, 6.0, and 4.9% of total radioactivity, respectively, i.e. no major metabolite was identified in plasma. Cenerimod was only detected in faeces and accounted for 17% of the radioactivity excreted in this matrix. The metabolite M32 was detected in both urine and faeces and represented 23% and 66% of radioactivity excreted in these matrices, respectively. Other metabolites of unknown structure were detected in small amounts. Overall, M32 and cenerimod accounted for 52% and 13%, respectively, of the total radioactivity recovered. Among the excreted metabolites, only the non-enzymatically formed M32 represented more than 25% of total drug-related material. Therefore, no pharmacokinetic drug–drug interaction studies are foreseen. [ABSTRACT FROM AUTHOR]

1. Darolutamide is a novel selective androgen receptor antagonist consisting of two pharmacologically equipotent diastereoisomers. The absorption, distribution, metabolism and excretion properties of darolutamide in rats are reported. 2. Non- or [14C]-labelled darolutamide, its diastereoisomers and major metabolite were studied in intact and bile duct-cannulated rats (oral and intravenous administration), and rat hepatocytes. 3. Darolutamide was quickly (1 h to reach maximum plasma concentration) and completely absorbed after oral administration. Absolute bioavailability was high. Keto-darolutamide was the most abundant metabolite in rat hepatocytes and the only major one in plasma. Interconversion between diastereoisomers was observed. 4. After oral administration, radioactivity distributed widely and homogeneously. Penetration into brain was low (brain/blood ratio = 0.079). Elimination was rapid from most tissues. Excretion occurred rapidly, and routes were similar irrespective of administration routes. Complete mass balance was reached by 168 h post-dose. Most radioactivity (61–64%) was excreted in faeces, while relevant amounts (30–33%) were also excreted into urine. The main clearance routes were metabolism via oxidative reactions and glucuronidation. After intravenous administration, a relevant extent of the dose (20%) underwent extrabiliary excretion as darolutamide. [ABSTRACT FROM AUTHOR]

The disposition and metabolism of prexasertib, a CHK-1 inhibitor was characterised over a 120 h period following a single 170-mg intravenous dose of [14C]prexasertib (50 µCi) to 6 patients with advanced/metastatic solid tumours. The prexasertib safety profile was consistent with prior studies. Plasma, urine, and faeces were analysed for radioactivity, prexasertib, and metabolites. Geometric mean t1/2 in plasma was 34.2 h for prexasertib and 73.8 h for total radioactivity. Unchanged prexasertib accounted for approximately 9% of plasma total radioactivity, indicating extensive metabolism by the presence of circulating metabolites. Both renal and faecal excretion were identified as important routes of elimination since 41.8% (±12.9%) of the total administered radioactivity was recovered in the renal excretions and 32.2% (±7.28%) in the faecal excretions. Mean renal clearance was approximately 15% of the total systemic clearance, while biliary clearance was also low. Prexasertib was cleared predominantly by metabolism with only 23% of the dose recovered in excreta as intact drug. Radioactivity was eliminated predominantly within 72 h in urine, but faecal elimination was protracted. The metabolism of prexasertib was complex while primary metabolic clearance pathways involved were oxidative deamination, O-dealkylation, mono-oxidation, and possibly direct glucuronide conjugation. Although prexasertib was the major component in plasma, up to 11 metabolites were observed. The most abundant metabolites identified in plasma were glucuronides and none of these are expected to contribute to the pharmacological activity or pose a safety concern. [ABSTRACT FROM AUTHOR]

1. Desloratadine is an antiallergic drug with species-dependent metabolic profiles in mice, rats, monkeys and humans. We investigated whether humanized-liver mice could reproduce the reported human-specific in vivo metabolic profile for desloratadine in terms of the formation of 3-hydroxydesloratadine and its O-glucuronide. 2. Hepatocytes prepared from humans and humanized-liver mice both preferentially catalyzed the formation of 3-hydroxydesloratadine and its O-glucuronide in vitro. 3. After a single oral administration of desloratadine, plasma levels of desloratadine and its metabolites (3-hydroxydesloratadine and its O-glucuronide) in humanized-liver mice were lower and higher, respectively, than those in control mice. 4. The amounts of 3-hydroxydesloratadine and its O-glucuronide excreted in humanized-liver mouse feces and urine were higher than those of the control mice, whereas 5- and 6-hydroxydesloratadine formation were predominant in the feces and urine samples from control mice. A significant correlation (r = 0.68) for the dose percentage of urinary and fecal metabolites of desloratadine was only observed between the humanized-liver mice and the reported values for humans. 5. These results indicated that urinary 3-hydroxydesloratadine O-glucuronide and fecal desloratadine, 3-hydroxydesloratadine and 5-hydroxydesloratadine were the major excretion pathways of desloratadine in humanized-liver mice, which is reasonably similar to that reported for humans. [ABSTRACT FROM AUTHOR]

2-Hydroxy-4-methoxybenzophenone (HMB) is a common ingredient in personal care products and used as an UV stabilizer. In these studies, disposition and metabolism of [14C]HMB in rats and mice was assessed following single gavage administration (10, 100, or 500 mg/kg), single IV administration (10 mg/kg), or dermal application (0.1, 1, 10, or 15 mg/kg). Following gavage administration, [14C]HMB was well absorbed and excreted mainly in urine (39–57%) and feces (24–42%) with no apparent difference between doses, species or sexes. Distribution of HMB in tissues was minimal in rats (0.36%) and mice (<0.55%). Distribution of HMB following dermal application was comparable to that following gavage administration; no differences between doses, sexes, or species were observed but absorption varied between dose vehicles. Light paraffin oil had the highest absorption and excretion (98% of the HMB dose absorbed). In rats, HMB slowly appeared in the systemic circulation (Tmax ∼2–6 h) and had poor bioavailability (F%<1). Urine metabolites for both species and all routes included HMB, HMB-glucuronide, 2,4-dihydroxybenzophenone (DHB), DHB-glucuronide, and DHB-sulfates, and novel minor dihydroxy metabolites including 2,5-dihydroxy-4-methoxybenzophenone. In vitro hepatic metabolism in mice differed from human and in vivo metabolism especially for phase II conjugates. [ABSTRACT FROM AUTHOR]

Bexagliflozin is a C-aryl glucoside inhibitor of human sodium-glucose linked transporter 2 (SGLT2) that undergoes oxidation and glucuronidation to form six principal metabolites in humans. In vitro metabolism by human liver microsomes and recombinant enzymes is primarily mediated by CYP3A4 and UGT1A9. Three major oxidation products and three major glucuronides have been identified in vivo. Metabolism by rats is mostly by oxidation whereas metabolism by monkeys and humans is mostly by glucuronidation. Metabolism by monkeys closely resembles metabolism by humans and all metabolites found in humans are also found in monkeys. A greater diversity of metabolites has been identified among human in vivo specimens than among in vitro reaction products. Following oral dosing of humans with 14C-bexagliflozin, the 3′-O-glucuronide contributed 32% of the parent AUC and all other metabolites contributed <10%. Of the 91.6% of input radioactivity recovered, 51.1% was in faeces, predominantly as bexagliflozin, and 40.5% was in urine, largely as the 3′-O-glucuronide. Unidentified metabolites contributed 0.27% of the input radiolabel. A quantitative accounting for the metabolism and disposition of bexagliflozin in vivo has been developed. [ABSTRACT FROM AUTHOR]

The P2Y12 receptor antagonist selatogrel which exhibits rapid inhibition of platelet aggregation following subcutaneous administration is in development for the treatment of acute myocardial infarction. This human ADME study was performed in six healthy male subjects to determine the routes of elimination and to identify/quantify the metabolites of selatogrel at a therapeutically relevant dose of 16 mg [14C]-radiolabelled selatogrel. The median tmax and t1/2 of selatogrel was 0.75 h and 4.7 h, respectively. It was safe and well tolerated based on adverse event, ECG, vital sign and laboratory data. Geometric mean total recovery of [14C]-radioactivity was 94.9% of which 92.5% was recovered in faeces and 2.4% in urine. Selatogrel was the most abundant entity in each matrix. In plasma, no major metabolite was identified. In excreta, the glucuronide M21 (14.7% of radioactivity) and the mono-oxidized A1 (6.2%) were the most abundant metabolites in urine and faeces, respectively. Overall, none of the metabolic pathways contributed to a relevant extent to the overall elimination of selatogrel, i.e. by more than 25% as defined per regulatory guidance. Hence, no pharmacokinetic interaction studies with inhibitors or inducers of drug-metabolizing enzymes are warranted for clinical development of selatogrel. [ABSTRACT FROM AUTHOR]

Sulfolane has been found as a ground water contaminant near refining sites. These studies investigated the in vitro hepatic clearance and in vivo disposition of [14C]sulfolane in rats and mice following a single oral administration (30, 100, or 300 mg/kg) and dermal application (100 mg/kg). [14C]Sulfolane was well-absorbed in male rats following oral administration and excreted extensively in urine (≥93%). Total radioactivity in tissues at 24 and 48 h was ∼7% and <2%. Disposition pattern was similar in female rats and male and female mice at 100 mg/kg oral dose. Dermally applied [14C]Sulfolane (covered dose site, 100 mg/kg) was poorly absorbed in male (∼16%) and female (∼19%) rats; absorption increased to 59% when the dose site was uncovered in male rats suggesting ingestion of dose via grooming of the dose site. Dermally applied [14C]sulfolane (100 mg/kg, covered dose site) was well absorbed in male (∼70%) and female (∼80%) mice. Urinary radiochemical profiles were similar between routes, species, and sexes; the main analytes present in urine were sulfolane and 3-hydroxysulfolane. Sulfolane was not cleared in hepatocytes from rodents or human suggesting sites other than liver might be involved in metabolism of sulfolane in vivo. [ABSTRACT FROM AUTHOR]

1. Ginkgolide B (GB), the most active of the ginkgolides, has been developed as a new drug for the treatment of vascular insufficiency; however, the pharmacokinetics of GB remain unclear. Here, we investigated the pharmacokinetics and urine excretion properties of GB in healthy Chinese subjects administered single- and multiple-dose injectable GB based on a new LC-MS/MS method. 2. GB pharmacokinetics were found to be dose-dependent from 20 to 60 mg. GB reached a steady state by day 6 with once-daily dosing at 40 mg. Systemic exposure to GB, as characterised by AUC0–∞, indicated accumulation following repeated once-daily dosing for seven consecutive days. The mean urinary cumulative excretion rate of GB in response to 20, 40, and 60 mg GB was 41.9 ± 18.5%, 32.9 ± 12.2%, and 43.9 ± 8.5%, respectively. 3. Dose-proportional pharmacokinetics of GB were observed after intravenous administration in healthy subjects. A gradual reduction in the volume of distribution and slight change in mean resistance time led us to conjecture the limited accumulation of GB based on distribution equilibrium in vivo. 4. This comprehensive study of the clinical pharmacokinetics of GB will provide useful information for its application and further development. [ABSTRACT FROM AUTHOR]

1. Mosapride is a potent gastroprokinetic agent, and des-p-fluorobenzyl mosapride (M1) and mosapride-N-oxide (M2) are its two major active metabolites. 2. The validated ultra-high performance liquid chromatography-tandem mass spectrometry method was successfully applied to the distribution and excretion of mosapride and its two active metabolites. 3. Mosapride and its metabolites were distributed widely and rapidly in various tissues. The highest concentration of mosapride and M2 in both male and female rats was found in the duodenum, followed by cecum. 4. The excretion study showed that a total of 71.8% (37.6, 22.4 and 11.8% for urine, feces and bile, respectively) and 66.3% (35.7, 22.8 and 7.8% for urine, feces and bile) of administered dose was recovered from male and female excreta. M1 was excreted in the largest dose percentage, followed by mosapride and M2, and the total cumulative excretion amounts were about 36.9, 28.1 and 11.6% in male rat, while 24.3, 25.9 and 16.2% in female rat. The results demonstrated for the first time that M2 is one of the important excretion forms of mosapride, which is much higher than that of mosapride in urine. 5. This work could provide valuable information for further pharmacological and clinical studies of mosapride. [ABSTRACT FROM AUTHOR]

1. The absorption, metabolism, and excretion of a single oral 450-mg dose of [14C]-(S)-6-(3-cyclopentyl-2-(4-trifluoromethyl)-1H-imidazol-1-yl)propanamido)nicotinic acid (PF-04991532), a hepatoselective glucokinase activator, was investigated in humans. Mass balance was achieved with ∼94.6% of the administered dose recovered in urine and feces. The total administered radioactivity excreted in feces and urine was 70.6% and 24.1%, respectively. Unchanged PF-04991532 collectively accounted for ∼47.2% of the dose excreted in feces and urine, suggestive of moderate metabolic elimination in humans. 2. The biotransformation pathways involved acyl glucuronidation (M1), amide bond hydrolysis (M3), and CYP3A4-mediated oxidative metabolism on the cyclopentyl ring in PF-04991532 yielding monohydroxylated isomers (M2a–d). Unchanged PF-04991532 was the major circulating component (64.4% of total radioactivity) whereas M2a–d collectively represented 28.9% of the total plasma radioactivity. 3. Metabolites M2a–d were not detected systemically in rats and dogs, the preclinical species for the toxicological evaluation of PF-04991532. In contrast, cynomologus monkeys dosed orally with unlabeled PF-04991532 revealed M2a–d in circulation, whose UV abundance was comparable to the profile in humans. This observation suggested that monkeys could potentially serve as a non-rodent alternative for studying the toxicity of PF-04991532 and its metabolites M2a–d. 4. The present results are in excellent agreement with our previously generated metabolite scouting data, which provided preliminary evidence for the disproportionate metabolism of PF-04991532 in humans. [ABSTRACT FROM AUTHOR]

The mass balance, pharmacokinetics and metabolism of rovatirelin were characterised in healthy male subjects after a single oral dose of [14C]rovatirelin. [14C]Rovatirelin was steadily absorbed, and the peak concentrations of radioactivity and rovatirelin were observed in plasma at 5–6 h after administration. The AUCinf of radioactivity was 4.9-fold greater than that of rovatirelin. Rovatirelin and its metabolite (thiazoylalanyl)methylpyrrolidine (TAMP) circulated in plasma as the major components. The total radioactivity recovered in urine and faeces was 89.0% of the administered dose. The principal route of elimination was excretion into faeces (50.1% of the dose), and urinary excretion was the secondary route (36.8%). Rovatirelin was extensively metabolised to 20 metabolites, and TAMP was identified as the major metabolite in plasma and excreta among its metabolites. To identify the metabolic enzymes responsible for TAMP formation, the in vitro activity was determined in human liver microsomes. The enzymatic activity depended on NADPH, and it was inhibited by ketoconazole. Furthermore, recombinant human cytochrome P450 (CYP) 3A4 and CYP3A5 displayed enzymatic activity in the assay. Therefore, CYP3A4/5 are the most important enzymes responsible for TAMP formation. [ABSTRACT FROM AUTHOR]

1. The metabolic fate and urinary excretion of 2-bromophenol, a phenolic metabolite of bromobenzene, was investigated in male Sprague–Dawley rats following single intraperitoneal doses at either 0, 100, or 200 mg/kg. 2. Urine was collected for seven days and samples analysed using 1 H NMR spectroscopy, inductively coupled plasma (ICP)MS, and UPLC-MS. 3. 1 H NMR spectroscopy of the urine samples showed that, at these doses, 2-bromophenol had little effect on endogenous metabolite profiles, supporting histopathology and clinical chemistry data, which showed no changes associated with the administration of 2-bromophenol in this study. 4. The use of ICP-MS provided a means for the selective detection and quantification of bromine-containing species and showed that between 15 and 30% of the dose was excreted via the urine over 7 days of the study for both the 100 and 200 mg doses, respectively. 5. The bulk of the excretion of Br-containing material had occurred by 8 h post administration. UPLC-MS of urine revealed a number of metabolites of 2-bromophenol, with 2-bromophenol glucuronide and 2-bromophenol sulphate identified as the major species. A number of minor hydroxylated metabolites were also detected as their glucuronide, sulphate, or O-methyl conjugates. There was no evidence for the production of reactive metabolites. [ABSTRACT FROM AUTHOR]

1. Naldemedine is a peripherally acting μ-opioid receptor antagonist for the treatment of opioid-induced constipation. 2. This phase 1 study investigated the absorption, distribution, metabolism and excretion of naldemedine, following a single oral 2-mg dose of [oxadiazole-14C]-naldemedine or [carbonyl-14C]-naldemedine to 12 healthy adult male subjects. Pharmacokinetic assessments were performed on blood, urine and fecal samples collected at defined intervals. 3. Naldemedine was the major circulating component in plasma with a median Tmax of approximately 0.8–0.9 h and a geometric mean t1/2,z of approximately 11 h. Total systemic exposures, AUC, of metabolites nor-naldemedine were less abundant than those of naldemedine (9% or 13% of AUC of naldemedine) and 16.2% or 18.1% of naldemedine was excreted as unchanged in urine after administration of [oxadiazole-14C]-naldemedine or [carbonyl-14C]-naldemedine, respectively, and benzamidine was the major radioactive component after administration of [oxadiazole-14C]-naldemedine (32.5% of administered dose). Overall, the recovery of total radioactivity was 92% (57.3% in urine; 34.8% in feces) after administration of [oxadiazole-14C]-naldemedine and 85% (20.4% in urine; 64.3% in feces) after administration of [carbonyl-14C]-naldemedine. 4. Our findings suggest that naldemedine is mainly metabolized to nor-naldemedine. Naldemedine was rapidly absorbed and well tolerated, with no major safety signals observed. [ABSTRACT FROM AUTHOR]

The absorption, metabolism and excretion of MT-1303 were investigated in healthy male subjects after a single oral dose of 0.4 mg [14C]-MT-1303 (ClinicalTrials.gov NCT02293967). The MT-1303 concentration in the plasma reached a maximum at 12 h after administration. Thereafter, the concentration declined with a half-life of 451 h. At the final assessment on Day 57, 91.16% of the administered radioactivity was excreted, and the cumulative excretion in the urine and faeces was 35.32% and 55.84%, respectively. The most abundant metabolite in plasma was MT-1303-P, which accounted for 42.6% of the area under the plasma concentration–time curve (AUC) of the total radioactivity. The major component excreted in urine was Human Urine (HU)4 (3066434), accounting for 28.1% of radioactivity in the sample (4.05% of the dose), whereas MT-1303 was a major component in the faeces, accounting for 89.8% of radioactivity in the sample (25.49% of the dose) up to 240 h after administration. This study indicates that multiple metabolic pathways are involved in the elimination of MT-1303 from the human body and the excretion of MT-1303 and MT-1303-P via the kidney is low. Therefore, MT-1303 is unlikely to cause conspicuous drug interactions or alter pharmacokinetics in patients with renal impairment. [ABSTRACT FROM AUTHOR]

1.The absorption, distribution, metabolism and excretion of enasidenib were studied following a single oral dose of [14C]enasidenib to rats (10 mg/kg; 100 μCi/kg) and healthy volunteers (100 mg; 318 nCi). 2.Enasidenib was readily absorbed, extensively metabolized and primarily eliminated via the hepatobiliary pathway. Enasidenib-derived radioactivity was widely distributed in rats. Excretion of radioactivity was approximately 95-99% of the dose from rats in 168 h post-dose and 82.4% from human volunteers in 504 h post-dose. In rat bile, approximately 35-42% of the administered dose was recovered, with less than 5% of the dose excreted as the parent drug. Renal elimination was a minor pathway, with <12% of the dose excreted in rat urine and <10% of the dose excreted in human urine. 3.Enasidenib was the prominent radioactive component in rat and human systemic circulation. Enasidenib was extensively metabolized in rats and human volunteers through N-dealkylation, oxidation, direct glucuronidation and combinations of these pathways. Glucuronidation was the major metabolic pathway in rats while N-dealkylation was the prominent metabolic pathway in human volunteers. All human metabolites were detected in rats. [ABSTRACT FROM AUTHOR]

1.Mesaconine, an ingredient from Aconitum carmichaelii Debx., has been proven to have cardiac effect. For further development and better pharmacological elucidation, the in vivo process and intestinal absorptive behavior of mesaconine should be investigated comprehensively. 2.An ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the quantitation of mesaconine in rat plasma, tissue homogenates, urine and feces to investigate the in vivo pharmacokinetic profiles, tissue distribution and excretion. The intestinal absorptive behavior of mesaconine was investigated using in vitro everted rat gut sac model. 3.Mesaconine was well distributed in tissues and a mass of unchanged form was detected in feces. It was difficultly absorbed into blood circulatory system after oral administration. The insufficient oral bioavailability of mesaconine may be mainly attributed to its low intestinal permeability due to a lack of lipophilicity. The absorption of mesaconine in rat's intestine is a first-order process with the passive diffusion mechanism. [ABSTRACT FROM AUTHOR]

1.The absorption, distribution, metabolism, and excretion of CC-223 were studied following a single oral dose of [14C]CC-223 to rats (3 mg/kg; 90 μCi/kg), dogs (1.5 mg/kg; 10 μCi/kg), and healthy volunteers (20 mg; 200 nCi). 2.CC-223-derived radioactivity was widely distributed in rats. Excretion of radioactivity was rapid and nearly complete from rats (87%), dogs (78%), and humans (97%). Feces was the major excretion pathway for rats (67%) and dogs (70%), whereas urine (57.6%) was the major elimination route for humans. Urine and bile each contained approximately 20% administered radioactivity in rats, whereas bile (20%) played a more important role than urine (<10%) in the excretion of absorbed radioactivity in dogs. Based on excretion data, CC-223 had good absorption, with greater than 56%, 29%, and 57% of the oral dose absorbed in rats, dogs, and humans, respectively. 3.CC-223 was the prominent radioactive component in circulation of rats (>71% of the exposure to total radioactivity) and dogs (≥45.5%), whereas M1 (76.5%) was the predominant circulating metabolite in humans. M1 and M1-derived metabolites accounted for >66% of human dose. CC-223 was extensively metabolized in rats, dogs, and humans through glucuronidation, O-demethylation, oxidation, and combinations of these pathways. [ABSTRACT FROM AUTHOR]