A new chronology for the Maori settlement of Aotearoa (NZ) and the potential role of climate change in demographic developments.

Understanding the role of climate change, resource availability, and population growth in human mobility remains critically important in anthropology. Researching linkages between climate and demographic changes during the short settlement history of Aotearoa (New Zealand) requires temporal precision equivalent to the period of a single generation. However, current modeling approaches frequently use small terrestrial radiocarbon datasets, a practice that obscures past Maori population patterns and their connection to changing climate. Our systematic analysis of terrestrial and marine 14C ages has enabled robust assessments of the largest dataset yet collated from island contexts. This analysis has been made possible by the recent development of a temporal marine correction for southern Pacific waters, and our findings show the shortcomings of previous models. We demonstrate that human settlement in the mid to late 13th century AD is unambiguous. We highlight initial (AD 1250 to 1275) settlement in the North Island. The South Island was reached a decade later (AD 1280 to 1295), where the hunting of giant flightless moa commenced (AD 1300 to 1415), and the population grew rapidly. Population growth leveled off around AD 1340 and declined between AD 1380 and 1420, synchronous with the onset of the Little Ice Age and moa loss as an essential food source. The population continued to grow in the more economically stable north, where conditions for horticulture were optimal. The enhanced precision of this research afforded by the robust analysis of marine dates opens up unique opportunities to investigate interconnectivity in Polynesia and inform the patterns seen in other island contexts.

A phase 1 open label study to assess the human mass balance and metabolite profile of 14C-fosmanogepix, a novel Gwt-1 inhibitor in healthy male participants.

Fosmanogepix [FMGX; active form manogepix (MGX)], a novel antifungal, is currently being studied for the treatment of invasive fungal diseases caused by Candida spp., Aspergillus spp., and other rare molds. This Phase 1, single-dose study used 14C-radiolabeled FMGX to determine the disposition and metabolism of FMGX. Ten healthy male participants were enrolled equally into: oral cohort {FMGX 500 mg oral + 3.1 megabecquerel [MBq, 84.0 microcurie (µCi)] 14C} and intravenous (IV) cohort [FMGX 600 mg IV + 3.4 MBq (93.0 µCi) 14C]. At the end of the sampling period (456 h post-dose), 90.2% of radioactivity administered was recovered (46.4% from urine; 43.8% from feces) in oral cohort (82.3% within 240 h), and 82.4% was recovered (42.5% from urine; 39.9% from feces) in IV cohort (76.2% within 264 h), indicating that FMGX elimination occurs via renal and hepatic routes. Radioactivity transformation pathways (oral and IV) indicated multiple major routes of metabolism of FMGX, mainly via MGX, and included oxidation, oxidative deamination, and conjugation. All except one key human plasma metabolite was observed in toxicity species, but its proportion (<10%) in the human area under the curve plasma samples was not of toxicological concern. No deaths, serious, or severe adverse events (AE) were reported, and there were no AE-related withdrawals. The results of this study indicated extensive metabolism of FMGX, with similar key human plasma metabolites observed in the animal studies. The elimination of FMGX was equally through renal and hepatic routes. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT04804059.

The effect of repeated hurricanes on the age of organic carbon in humid tropical forest soil.

Increasing hurricane frequency and intensity with climate change is likely to affect soil organic carbon (C) stocks in tropical forests. We examined the cycling of C between soil pools and with depth at the Luquillo Experimental Forest in Puerto Rico in soils over a 30-year period that spanned repeated hurricanes. We used a nonlinear matrix model of soil C pools and fluxes ("soilR") and constrained the parameters with soil and litter survey data. Soil chemistry and stable and radiocarbon isotopes were measured from three soil depths across a topographic gradient in 1988 and 2018. Our results suggest that pulses and subsequent reduction of inputs caused by severe hurricanes in 1989, 1998, and two in 2017 led to faster mean transit times of soil C in 0-10 cm and 35-60 cm depths relative to a modeled control soil with constant inputs over the 30-year period. Between 1988 and 2018, the occluded C stock increased and δ13C in all pools decreased, while changes in particulate and mineral-associated C were undetectable. The differences between 1988 and 2018 suggest that hurricane disturbance results in a dilution of the occluded light C pool with an influx of young, debris-deposited C, and possible microbial scavenging of old and young C in the particulate and mineral-associated pools. These effects led to a younger total soil C pool with faster mean transit times. Our results suggest that the increasing frequency of intense hurricanes will speed up rates of C cycling in tropical forests, making soil C more sensitive to future tropical forest stressors.

Peatland pools are tightly coupled to the contemporary carbon cycle.

Peatlands are globally important stores of soil carbon (C) formed over millennial timescales but are at risk of destabilization by human and climate disturbance. Pools are ubiquitous features of many peatlands and can contain very high concentrations of C mobilized in dissolved and particulate organic form and as the greenhouses gases carbon dioxide (CO2 ) and methane (CH4 ). The radiocarbon content (14 C) of these aquatic C forms tells us whether pool C is generated by contemporary primary production or from destabilized C released from deep peat layers where it was previously stored for millennia. We present novel 14 C and stable C (δ13 C) isotope data from 97 aquatic samples across six peatland pool locations in the United Kingdom with a focus on dissolved and particulate organic C and dissolved CO2 . Our observations cover two distinct pool types: natural peatland pools and those formed by ditch blocking efforts to rewet peatlands (restoration pools). The pools were dominated by contemporary C, with the majority of C (~50%-75%) in all forms being younger than 300 years old. Both pool types readily transform and decompose organic C in the water column and emit CO2 to the atmosphere, though mixing with the atmosphere and subsequent CO2 emissions was more evident in natural pools. Our results show little evidence of destabilization of deep, old C in natural or restoration pools, despite the presence of substantial millennial-aged C in the surrounding peat. One possible exception is CH4 ebullition (bubbling), with our observations showing that millennial-aged C can be emitted from peatland pools via this pathway. Our results suggest that restoration pools formed by ditch blocking are effective at preventing the release of deep, old C from rewetted peatlands via aquatic export.

Highland deer mice support increased thermogenesis in response to chronic cold hypoxia by shifting uptake of circulating fatty acids from muscles to brown adipose tissue.

During maximal cold challenge (cold-induced V̇O2,max) in hypoxia, highland deer mice (Peromyscus maniculatus) show higher rates of circulatory fatty acid delivery compared with lowland deer mice. Fatty acid delivery also increases with acclimation to cold hypoxia (CH) and probably plays a major role in supporting the high rates of thermogenesis observed in highland deer mice. However, it is unknown which tissues take up these fatty acids and their relative contribution to thermogenesis. The goal of this study was to determine the uptake of circulating fatty acids into 24 different tissues during hypoxic cold-induced V̇O2,max, by using [1-14C]2-bromopalmitic acid. To uncover evolved and environment-induced changes in fatty acid uptake, we compared lab-born and -raised highland and lowland deer mice, acclimated to either thermoneutral (30°C, 21 kPa O2) or CH (5°C, 12 kPa O2) conditions. During hypoxic cold-induced V̇O2,max, CH-acclimated highlanders decreased muscle fatty acid uptake and increased uptake into brown adipose tissue (BAT) relative to thermoneutral highlanders, a response that was absent in lowlanders. CH acclimation was also associated with increased activities of enzymes citrate synthase and ß-hydroxyacyl-CoA dehydrogenase in the BAT of highlanders, and higher levels of fatty acid translocase CD36 (FAT/CD36) in both populations. This is the first study to show that cold-induced fatty acid uptake is distributed across a wide range of tissues. Highland deer mice show plasticity in this fatty acid distribution in response to chronic cold hypoxia, and combined with higher rates of tissue delivery, this contributes to their survival in the cold high alpine environment.

Sulfamethoxazole is Metabolized and Mineralized at Extremely Low Concentrations.

The presence of organic micropollutants in water and sediments motivates investigation of their biotransformation at environmentally low concentrations, usually in the range of µg L-1. Many are biotransformed by cometabolic mechanisms; however, there is scarce information concerning their direct metabolization in this concentration range. Threshold concentrations for microbial assimilation have been reported in both pure and mixed cultures from different origins. The literature suggests a range value for bacterial growth of 1-100 µg L-1 for isolated aerobic heterotrophs in the presence of a single substrate. We aimed to investigate, as a model case, the threshold level for sulfamethoxazole (SMX) metabolization in pure cultures of Microbacterium strain BR1. Previous research with this strain has covered the milligram L-1 range. In this study, acclimated cultures were exposed to concentrations from 0.1 to 25 µg L-1 of 14C-labeled SMX, and the 14C-CO2 produced was trapped and quantified over 24 h. Interestingly, SMX removal was rapid, with 98% removed within 2 h. In contrast, mineralization was slower, with a consistent percentage of 60.0 ± 0.7% found at all concentrations. Mineralization rates increased with rising concentrations. Therefore, this study shows that bacteria are capable of the direct metabolization of organic micropollutants at extremely low concentrations (sub µg L-1).

Fossil and Nonfossil Sources of Winter Organic Aerosols in the Regional Background Atmosphere of China.

Carbonaceous aerosols (CA) from anthropogenic emissions have been significantly reduced in urban China in recent years. However, the relative contributions of fossil and nonfossil sources to CA in rural and background regions of China remain unclear. In this study, the sources of different carbonaceous fractions in fine aerosols (PM2.5) from five background sites of the China Meteorological Administration Atmosphere Watch Network during the winter of 2019 and 2020 were quantified using radiocarbon (14C) and organic markers. The results showed that nonfossil sources contributed 44-69% to total carbon at these five background sites. Fossil fuel combustion was the predominant source of elemental carbon at all sites (73 ± 12%). Nonfossil sources dominated organic carbon (OC) in these background regions (61 ± 13%), with biomass burning or biogenic-derived secondary organic carbon (SOC) as the most important contributors. However, the relative fossil fuel source to OC in China (39 ± 13%) still exceeds those at other regional/background sites in Asia, Europe, and the USA. SOC dominated the fossil fuel-derived OC, highlighting the impact of regional transport from anthropogenic sources on background aerosol levels. It is therefore imperative to develop and implement aerosol reduction policies and technologies tailored to both the anthropogenic and biogenic emissions to mitigate the environmental and health risks of aerosol pollution across China.

Synthesis of Radiolabeled [14C]Rimsulfuron and Stable Isotope Labeled Rimsulfuron-[M + 3] to Support Crop Metabolism Studies for Reregistration.

Rimsulfuron is a sulfonylurea herbicide that controls grass and broadleaf weeds in maize, potatoes, fruits, nuts, and other crops. It can also be used as a burndown herbicide to clear invasive weed species along roadsides and other nonagricultural land. Rimsulfuron acts as an acetolactase synthase (ALS) inhibitor, blocking the synthesis of essential amino acids required for plant growth. As is common practice, rimsulfuron has been subject to periodic reviews by regulatory agencies for reregistration since its introduction into the market in the early 1990s. The goal of these reviews is to ensure that the herbicide carries out its intended use without creating adverse side effects to humans and the environment. Since scientific methods are continually evolving and being developed, global regulatory agencies can require additional studies to address data gaps for pesticide renewals. During this reregistration process for rimsulfuron, a new confined rotational crop study was required to address a data gap requested by the European Food Safety Authority (EFSA). Consequently, the corresponding pyridine and pyrimidine radiolabeled [14C]rimsulfuron and [M + 3] stable isotopes of rimsulfuron were synthesized for this study to support the reregistration process.

Molecular 14 C evidence for contrasting turnover and temperature sensitivity of soil organic matter components.

Climate projection requires an accurate understanding for soil organic carbon (SOC) decomposition and its response to warming. An emergent view considers that environmental constraints rather than chemical structure alone control SOC turnover and its temperature sensitivity (i.e., Q10 ), but direct long-term evidence is lacking. Here, using compound-specific radiocarbon analysis of soil profiles along a 3300-km grassland transect, we provide direct evidence for the rapid turnover of lignin-derived phenols compared with slower-cycling molecular components of SOC (i.e., long-chain lipids and black carbon). Furthermore, in contrast to the slow-cycling components whose turnover is strongly modulated by mineral association and exhibits low Q10 , lignin turnover is mainly regulated by temperature and has a high Q10 . Such contrasts resemble those between fast-cycling (i.e., light) and mineral-associated slow-cycling fractions from globally distributed soils. Collectively, our results suggest that warming may greatly accelerate the decomposition of lignin, especially in soils with relatively weak mineral associations.

FOXO1 promotes endothelial cell elongation and angiogenesis by up-regulating the phosphorylation of myosin light chain 2.

The forkhead box O1 (FOXO1) is an important transcription factor related to proliferation, metabolism, and homeostasis, while the major phenotype of FOXO1-null mice is abnormal vascular morphology, such as vessel enlargement and dilation. In in vitro mouse embryonic stem cell (ESC)-differentiation system, Foxo1-/- vascular endothelial cells (ECs) fail to elongate, and mimic the abnormalities of FOXO1-deficiency in vivo. Here, we identified the PPP1R14C gene as the FOXO1 target genes responsible for elongating using transcriptome analyses in ESC-derived ECs (ESC-ECs), and found that the FOXO1-PPP1R14C-myosin light chain 2 (MLC2) axis is required for EC elongation during angiogenesis. MLC2 is phosphorylated by MLC kinase (MLCK) and dephosphorylated by MLC phosphatase (MLCP). PPP1R14C is an inhibitor of PP1, the catalytic subunit of MLCP. The abnormal morphology of Foxo1-/- ESC-ECs was associated with low level of PPP1R14C and loss of MLC2 phosphorylation, which were reversed by PPP1R14C-introduction. Knockdown of either FOXO1 or PPP1R14C suppressed vascular cord formation and reduced MLC2 phosphorylation in human ECs (HUVECs). The mouse and human PPP1R14C locus possesses an enhancer element containing conserved FOXO1-binding motifs. In vivo chemical inhibition of MLC2 phosphorylation caused dilated vascular structures in mouse embryos. Furthermore, foxo1 or ppp1r14c-knockdown zebrafish exhibited vascular malformations, which were also restored by PPP1R14C-introduction. Mechanistically, FOXO1 suppressed MLCP activity by up-regulating PPP1R14C expression, thereby promoting MLC2 phosphorylation and EC elongation, which are necessary for vascular development. Given the importance of MLC2 phosphorylation in cell morphogenesis, this study may provide novel insights into the role of FOXO1 in control of angiogenesis.

Cover crop root morphology rather than quality controls the fate of root and rhizodeposition C into distinct soil C pools.

Cover crops increase carbon (C) inputs to agricultural soils, and thus have the potential to mitigate climate change through enhanced soil organic carbon (SOC) storage. However, few studies have explored the fate of belowground C inputs associated with varying root traits into the distinct SOC pools of mineral-associated organic carbon (MAOC) particulate organic carbon (POC). Therefore, a packed 0.5 m column trial was established with 0.25 m topsoil and 0.25 m subsoil with four cover crops species (winter rye, oilseed radish, chicory, and hairy vetch) known to differ in C:N ratio and root morphology. Cover crops were 14 CO2 -labeled for 3 months, and then, half of the columns were sampled to quantify root and rhizodeposition C. In the remaining columns, plant shoots were harvested and the undisturbed soil and roots were left for incubation. Bulk soil from both sampling times was subjected to a simple fractionation scheme, where 14 C in the <50 and >50 µm fraction was assumed to represent MAOC and POC, respectively. The fast-growing rye and radish produced the highest root C. The percentage loss of C via rhizodeposition (%ClvR) showed a distinct pattern, with 22% for the more branched roots (rye and vetch) and 6%-8% for the less branched roots (radish and chicory). This suggests that root morphology plays a key role in determining rhizodeposition C. After 1 year of incubation at room temperature, the remaining MAOC and POC were positively correlated with belowground inputs in absolute terms. However, topsoil MAOC formation efficiencies (cover crop-derived MAOC remaining as a share of belowground inputs) were higher for vetch and rye (21% and 15%, respectively) than for chicory and radish (9% and 10%, respectively), suggesting a greater importance of rhizodeposition (or indirectly, root morphology) than solely substrate C:N ratio for longer term C stabilization.

A phase 1 study to investigate the absorption, distribution, metabolism and excretion of brepocitinib in healthy males using a 14 C-microdose approach.

AIMS: Brepocitinib is a tyrosine kinase 2/Janus kinase 1 inhibitor being investigated for the treatment of several autoimmune diseases. This study assessed the absorption, distribution, metabolism and excretion of oral brepocitinib, and the absolute oral bioavailability (F) and fraction absorbed (Fa ) using a 14 C microtracer approach. METHODS: This was a phase 1 open-label, nonrandomized, fixed sequence, two-period, single-dose study of brepocitinib in healthy male participants. Participants received a single oral 60 mg dose of 14 C brepocitinib (~300 nCi) in Period A, then an unlabelled oral 60 mg dose followed by an intravenous (IV) 30 µg dose of 14 C labelled brepocitinib (~300 nCi) in Period B. Mass balance, pharmacokinetic parameters and safety were assessed. RESULTS: Six participants were enrolled. Brepocitinib was absorbed rapidly following oral administration. In Period A, total recovery of the oral dose was 96.7% ± 6.3% (88.0% ± 8.0% in urine, 8.7% ± 2.1% in faeces). In Period B, a small fraction (6.0% of the oral dose) was recovered unchanged in urine. F and Fa were 74.6% (90% confidence interval 67.3%, 82.8%) and 106.9%, respectively. Brepocitinib demonstrated an acceptable safety profile and was well tolerated following oral or oral then IV administrations. No deaths, serious adverse events or discontinuations were reported. CONCLUSION: Intestinal absorption of brepocitinib was essentially complete after oral administration, with F ~75%. Drug-related material recovery was high, with the majority excreted in urine. The major route of elimination of brepocitinib was renal excretion as metabolites, whereas urinary elimination of unchanged brepocitinib was minor. NCT: NCT03770039.

Anthropogenic Disturbance Stimulates the Export of Dissolved Organic Carbon to Rivers on the Tibetan Plateau.

The impacts of human activities on the riverine carbon (C) cycle have only recently been recognized, and even fewer studies have been reported on anthropogenic impacts on C cycling in rivers draining the vulnerable alpine areas. Here, we examined carbon isotopes (δ13CDOC and Δ14CDOC), fluorescence, and molecular compositions of riverine dissolved organic matters (DOM) in the Bailong River catchment, the eastern edge of the Tibetan Plateau to identify anthropogenic impacts on the C cycle. Human activities show limited impact on dissolved organic carbon (DOC) concentration, but significantly increased the age of DOC (from modern to ∼1600 yr B.P.) and changed the molecular compositions through agriculture and urbanization despite in the catchment with low population density. Agricultural activities indirectly increased the leaching of N-containing aged organic matter from deep soil to rivers. Urbanization released S-containing aged C from fossil products into rivers directly through wastewater. The aged DOC from agricultural activity and wastewater discharge was partly biolabile and/or photolabile. This study highlights that riverine C is sensitive to anthropogenic disturbance. Additionally, the study also emphasizes that human activities reintroduce aged DOC into the modern C cycle, which would accelerate the geological C cycle.

A special issue preface: Radiocarbon in the Anthropocene.

The Anthropocene is defined by marked acceleration in human-induced perturbations to the Earth system. Anthropogenic emissions of CO2 and other greenhouse gases to the atmosphere and attendant changes to the global carbon cycle are among the most profound and pervasive of these perturbations. Determining the magnitude, nature and pace of these carbon cycle changes is crucial for understanding the future climate that ecosystems and humanity will experience and need to respond to. This special issue illustrates the value of radiocarbon as a tool to shed important light on the nature, magnitude and pace of carbon cycle change. This article is part of the Theo Murphy meeting issue 'Radiocarbon in the Anthropocene'.

Making the case for an International Decade of Radiocarbon.

Radiocarbon (14C) is a critical tool for understanding the global carbon cycle. During the Anthropocene, two new processes influenced 14C in atmospheric, land and ocean carbon reservoirs. First, 14C-free carbon derived from fossil fuel burning has diluted 14C, at rates that have accelerated with time. Second, 'bomb' 14C produced by atmospheric nuclear weapon tests in the mid-twentieth century provided a global isotope tracer that is used to constrain rates of air-sea gas exchange, carbon turnover, large-scale atmospheric and ocean transport, and other key C cycle processes. As we write, the 14C/12C ratio of atmospheric CO2 is dropping below pre-industrial levels, and the rate of decline in the future will depend on global fossil fuel use and net exchange of bomb 14C between the atmosphere, ocean and land. This milestone coincides with a rapid increase in 14C measurement capacity worldwide. Leveraging future 14C measurements to understand processes and test models requires coordinated international effort-a 'decade of radiocarbon' with multiple goals: (i) filling observational gaps using archives, (ii) building and sustaining observation networks to increase measurement density across carbon reservoirs, (iii) developing databases, synthesis and modelling tools and (iv) establishing metrics for identifying and verifying changes in carbon sources and sinks. This article is part of the Theo Murphy meeting issue 'Radiocarbon in the Anthropocene'.

Pharmacokinetics, mass balance, and metabolism of [14C]TPN171, a novel PDE5 inhibitor, in humans for the treatment of pulmonary arterial hypertension.

TPN171 is a novel phosphodiesterase-5 (PDE5) inhibitor used to treat pulmonary arterial hypertension (PAH) and erectile dysfunction (ED), which currently is undergoing phase II clinical trials in China. In this single-center, single-dose, nonrandomized, and open design study, radiolabeled [14C]TPN171 was used to investigate the metabolic mechanism, pharmacokinetic characteristics, and clearance pathways of TPN171 in 6 healthy Chinese male volunteers. Each volunteer was administered a single oral suspension of 10 mg (100 µCi) of [14C]TPN171. We found that TPN171 was absorbed rapidly in humans with a peak time (Tmax) of 0.667 h and a half-life (t1/2) of approximately 9.89 h in plasma. Excretion of radiopharmaceutical-related components was collected 216 h after administration, accounting for 95.21% of the dose (46.61% in urine and 48.60% in feces). TPN171 underwent extensive metabolism in humans. Twenty-two metabolites were detected in human plasma, urine, and feces using a radioactive detector combined with a high-resolution mass spectrometer. According to radiochromatograms, a glucuronide metabolite of O-dealkylated TPN171 exceeded 10% of the total drug-related components in human plasma. However, according to the Food and Drug Administration (FDA) guidelines, no further tests are needed to evaluate the safety of this metabolite because it is a phase II metabolite, but the compound is still worthy of attention. The main metabolic biotransformation of TPN171 was mono-oxidation (hydroxylation and N-oxidation), dehydrogenation, N-dealkylation, O-dealkylation, amide hydrolysis, glucuronidation, and acetylation. Cytochrome P450 3A4 (CYP3A4) mainly catalyzed the formation of metabolites, and CYP2E1 and CYP2D6 were involved in the oxidative metabolism of TPN171 to a lesser extent. According to the incubation data, M1 was mainly metabolized to M1G by UDP-glucuronosyltransferase 1A9 (UGT1A9), followed by UGT1A7 and UGT1A10.

Sequential loss-on-ignition as a simple method for evaluating the stability of soil organic matter under actual environmental conditions.

Soil organic matter (SOM) is one of the largest carbon (C) reservoirs on Earth, and therefore its stability attracts a great deal of interest from the perspective of the global C cycle. This study examined the applicability of loss-on-ignition with a stepwise increase in temperature (SIT-LOI) of soil to evaluate the stability of SOM using soil samples having different organic matter (OM) and mineral contents and different mean residence times (MRTs) for SOM. The responses of SOM to the SIT-LOI varied depending on the samples but were all successfully approximated by a liner regression model as a function of the temperature of LOI. The slope value in the liner model that determines the residual potential of carbon during the SIT-LOI highly correlated with MRT of SOM, suggesting that this value reflects the overall stability of SOM over a range of soil properties. This hypothesis was consistent with the observation that Δ14C values of SOM decreased with increasing LOI temperature and thus, older, slower-cycling SOM was preferentially left in the soil samples by SIT-LOI. Additionally, the hypothesis was also supported by the significant correlations (p < 0.01) between the slope value and OM and mineral contents in the samples because these components are considered to regulate SOM stability. In addition to the regression analysis of the SIT-LOI data, changes in carbon to nitrogen (C/N) and carbon to hydrogen (C/H) ratios and stable carbon isotope signatures (δ13C) of the samples were investigated. The results suggest that the mineral association of SOM is an important factor characterizing the response of SOM to LOI. Hence, it was concluded that SIT-LOI is a simple and useful method for evaluating the stability of SOM under actual environmental conditions.

Mass balance study of [14C]SHR0302, a selective and potent JAK1 inhibitor in humans.

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.

Determination of enzymatic kinetics of metabolism of dimethoate and omethoate in rats and humans.

1. Dimethoate is an organophosphate insecticide. The objective of this work was to determine the enzymatic kinetics of metabolism of dimethoate and its active metabolite omethoate in rats and humans and obtain key input parameters for physiologically based pharmacokinetic (PBPK) model.2. First, the intrinsic clearance of dimethoate expressed as formation rate of omethoate was determined to be ∼42-fold lower in human liver microsomes (HLM) (0.39 µL/min/mg) than in rat liver microsomes (RLM) (16.6 µL/min/mg) by an LC/MS/MS method. Next, dimethoate clearance in liver microsomes was determined using parent depletion and total [14C]-metabolite formation methods. Results from both approaches showed slower clearance of dimethoate in HLM (1.1-3.3 µL/min/mg) than in RLM (12.7-17.4 µL/min/mg).3. Investigation of in vitro enzymatic kinetics of omethoate demonstrated that the intrinsic clearance rates for omethoate in adult and juvenile RLM and HLM were similar. No significant turnover of dimethoate was apparent in rat cytosol or plasma. In contrast, degradation of omethoate in human plasma was slightly higher than in rat plasma.4. Finally, toxicokinetics of dimethoate were determined in adult and juvenile rats. In both age groups, following oral dosing, absorption of dimethoate was rapid with formation of significant amounts of omethoate.

ADME properties of CHF6366, a novel bi-functional M3 muscarinic receptor antagonist and ß2 adrenoceptor agonist (MABA) radiolabelled at both functional moieties.

CHF6366, a dual action ß2-receptor agonist and M3-muscarinic receptor antagonist developed for chronic obstructive pulmonary disease (COPD) was [14C]-radiolabelled on the two different functional moieties of the molecule (either aminobutanolic or carbamate) to characterise its ADME profile following intravenous (IV), intratracheal (IT) and oral (PO) administration.A very low oral bioavailability and a good balance between absorption and lung retention after IT administration were observed, together with a rapid distribution throughout the body and a complete metabolic transformation of the parent drug without relevant gender difference.CHF6366 was observed fully hydrolysed to alcohol (CHF6387) and carboxylic acid (CHF6361) in plasma and urine after IV and IT administration, and mainly unchanged in faeces only after oral administration. An important number of metabolites containing aminobutanolic moiety was excreted via urine, whereas carbamate-containing derivatives were excreted mainly by bile.The major metabolic routes of the alcoholic moiety (CHF6387) included isomerisation (Ma7), conjugation with glucuronic acid and dehydrogenation, while the carboxylic acid moiety (CHF6361) was mainly metabolised through oxidation, glucuronide conjugation and, in both pathways, combinations of those metabolic reactions.No major differences arose also from in vitro metabolism profiles investigated using liver microsomes and hepatocytes of different species.