Total Radioactivity Research Articles

Rapid screening technique for gross α and gross β estimations in aqueous samples during radiation emergency

Abstract A portable liquid scintillation counting system has been used as a rapid screening tool for radiological characterization and in situ measurements of aqueous samples. The methodology was standardized based on the Pulse Length Index for gross α and gross β activity determinations in aqueous solutions by means of a portable Liquid Scintillation Counter (LSC). This single compact PMT system yielded precise results for aqueous test samples, which were validated against a conventional HIDEX 300SL LSC system. The sensitivity of the portable LSC for gross measurements was investigated thoroughly for various combinations of scintillation cocktails and sample proportions, and found to be well below the Operational Intervention Levels (OILs) recommended by Atomic Energy Regulatory Board (AERB) during radiation emergency scenarios. Gross α- and β-activity measurements by means of the portable LSC system have shown this procedure to be effective for preliminary screening and evaluating the total radioactivity in aqueous samples during such radiation emergencies.

A Phase I, Open-Label, Mass Balance Study of [14C]-Iberdomide in Healthy Subjects.

Iberdomide is a novel potent cereblon modulator (CELMoD®) agent, which is currently under clinical development for hematological malignancies. A human mass balance study was conducted to characterize the biotransformation and excretion pathways of iberdomide. After a single dose of radiolabelled [14C]-iberdomide (1 mg) in six healthy subjects. Blood, urine, and fecal samples were collected for pharmacokinetics, mass balance, and clinical laboratory assessments. Results showed that a single oral dose of 1 mg iberdomide was generally well tolerated in healthy subjects. The recovery of [14C]-iberdomide-derived radioactivity in humans was 45.9% in urine and 42.6% in feces. Based on exposure (area under the concentration-time curve [AUC0-24]), iberdomide and M12 (metabolites) accounted for approximately 59% and 14% of circulating total radioactivity (TRA) exposure, respectively. Of the 88.5% TRA excreted, approximately 27% was excreted as unchanged iberdomide and 62% as metabolites, with similar amounts of excreted metabolites in the urine (16%) and feces (11%). Biotransformation of iberdomide in humans included multiple oxidations of the morpholino moiety as well as glutarimide ring hydrolysis of parent and oxidized metabolites and a combination of these pathways. Iberdomide was the predominant component in human plasma, with metabolite M12 being the most prominent circulating metabolite. In excreta, similar iberdomide-derived radioactivity was found in urine and feces. NCT03294603.

Pharmacokinetics, mass balance, and metabolism of [14C]envonalkib (TQ-B3139), a novel ALK tyrosine kinase inhibitor, in healthy Chinese subjects.

Envonalkib (TQ-B3139) is a novel, potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor used to treat ALK-positive non-small cell lung cancer. This phase I mass balance study investigated the pharmacokinetics, metabolism, and excretion of 14C-radiolabeled envonalkib in healthy Chinese male subjects. A single oral dose of 600mg (150µCi) [14C]envonalkib was administered to healthy male subjects under fasted state. Samples of blood, urine and feces were collected for quantitative determination of total radioactivity and unchanged envonalkib, and the metabolites identification. After dosing, the median Tmax of radioactivity was 4h and the mean t1/2 was 65.2h in plasma. The exposure of total radioactivity was much higher than that of unchanged envonalkib in plasma. The mean total recovery of the radiolabeled dose was 93.93% over 504h post-dose, with 15.23% in urine and 78.71% in feces. Envonalkib underwent extensive metabolism and a total of 15 metabolites were identified in plasma, urine, and feces. Unchanged envonalkib and its major metabolite M315 were the main components in plasma, accounting for 20.37% and 33.33% of total plasma radioactivity. In urine, O-dealkylation metabolite M315 was the major component accounted for 7.98% of dose. In feces, 16.01% of dose was excreted as cysteine conjugate M434-1. Envonalkib was well tolerated and there were no serious adverse events observed in the study. Envonalkib was extensively metabolized prior to excretion and eliminated primarily as metabolites via feces.

Radioactivity in the Southern East Baghdad Oilfield from the Reservoir to the Surface Environment

Naturally occurring radioactivity was evaluated in the reservoir rock, surface soil samples, and oil production waste at the East Baghdad South (EBS) Oil Field. The radioactivity of uranium-238 (and radium-226), thorium-232, and potassium-40 were calculated in core samples from four geological formations: Al-Zubair, Al-Khasib, Tanuma, and Hartha Formations, which represent the oil reservoirs in the study area in addition to the natural GR and SGR logs for the oil well in EBS were calculated. The radioactivity of the above-mentioned nuclides was also measured for surface soil samples and waste samples from the site of the oil production industry at the EBS oilfield. The measurements included all the stages of oil production from the collection of crude oil from the wells stage to the storage of the manufactured oil. It also included measurements of radioactivity in samples for some sites outside the industry and near the oil wells in the region. Total radioactivity was measured in count/second and the exposure dose rates were also measured at all the above sites. Relatively high concentrations of uranium-238 and radium-226 were found in rock core samples of some geological units within the oil reservoir formations which will certainly move with the oil to the surface and collect with waste (such as sludge) when oil is produced. Although, some sites have higher Ra-226, Th-232, and K-40, in the sludge samples and oily soil, such as in the 1st separator stage, water separation (Desalter) stage, and near the waste pit, these locations are acceptable if they are compared with other oilfields worldwide. The gamma absorbed doses calculated inside the EBS oil industry were higher than the global average of (59) nGy/h where Ra-226 is the main contributor in these doses, on the other hand, external hazard index (Hex) values less than unity so they are acceptable according to UNSCEAR. Radiation dose values in some places in the study area exceed the values recommended by ICRP, UNSCEAR, and IAEA (1 mSv/y) for the public but less than the values recommended for workers (20 mSv/y). generally, the site of EBS- oilfield does not show radioactive contamination or significant radioactive hazards, as it is a new facility, and safety instructions are still strictly applied, and the removal of waste immediately before its spread by the activity of the workers in the facility.

Radiolabel Uncovers Nonintuitive Metabolites of BIIB104: Novel Release of [14C]Cyanide from 2-Cyanothiophene and Subsequent Formation of [14C]Thiocyanate.

BIIB104 (formerly PF-04958242), N-((3S,4S)-4-(4-(5-cyanothiophen-2-yl)phenoxy)tetrahydrofuran-3-yl)propane-2-sulfonamide, is an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiator investigated for the treatment of cognitive impairment associated with schizophrenia. Preliminary in vitro metabolism studies with non-radiolabeled BIIB104 in rat, dog, and human liver microsomes (RLM, DLM, and HLM) showed O-dealkylation in all three species, tetrahydrofuran hydroxylation dominating in DLM and HLM, and thiophene hydroxylation prevalent in RLM. However, a subsequent rat mass balance study with [nitrile-14C]BIIB104 showed incomplete recovery of administered radioactivity (∼80%) from urine and feces over 7 days following an oral dose, and an exceptionally long plasma total radioactivity half-life. Radiochromatographic metabolite profiling and identification, including chemical derivation, revealed that [14C]cyanide was a major metabolite of [nitrile-14C]BIIB104 in RLM, but a minor and trace metabolite in DLM and HLM, respectively. Correspondingly in bile duct-cannulated rats, [14C]thiocyanate accounted for ∼53% of total radioactivity excreted over 48 hours postdose and it, as an endogenous substance, explained the exceptionally long plasma radioactivity half-life. The release of [14C]cyanide from the 2-cyanothiophene moiety is postulated to follow an epoxidation-initiated thiophene-opening based on the detection of non-radiolabeled counterpart metabolites in RLM. This unusual biotransformation serves as a lesson regarding placement of the radioactive label on an aryl nitrile when material will be used for evaluating the metabolism of a new drug candidate. Additionally, the potential cyanide metabolite of nitrile-containing drug molecules may be detected in liver microsomes with liquid chromatography-mass spectrometry following a chemical derivatization. SIGNIFICANCE STATEMENT: Using [nitrile-14C]BIIB104, non-intuitive metabolites of BIIB104 were discovered involving a novel cyanide release from the 2-cyanothiophene motif via a postulated epoxidation-initiated thiophene-opening. This unusual biotransformation serves as a lesson regarding placement of the radioactive label on an aryl nitrile when material will be used for evaluating the metabolism of a new drug candidate.

Understanding the pharmacokinetic journey of Fc-fusion protein, rhIL-7-hyFc using complementary approach of two analytical methods, accelerator mass spectrometry and ELISA.

Antibody-based therapeutics (ABTs), including monoclonal/polyclonal antibodies and fragment crystallizable region (Fc)-fusion proteins, are increasingly used in disease treatment, driving the global market growth. Understanding the pharmacokinetic (PK) properties of ABTs is crucial for their clinical effectiveness. This study investigated the PK profile and tissue distribution of efineptakin alfa, a long-acting recombinant human interleukin-7 (rhIL-7-hyFc), using enzyme-linked immunosorbent assay (ELISA) and accelerator mass spectrometry (AMS). Totally, four rats were injected intramuscularly with 1mg/kg of rhIL-7-hyFc containing 14C-rhIL-7-hyFc, which was prepared via reductive methylation. Serum total radioactivity (TRA) and serum rhIL-7-hyFc concentrations were quantified using AMS and ELISA, respectively. The TRA concentrations in organs were determined by AMS. Serum TRA peaked at 10hours with a terminal half-life of 40hours. The rhIL-7-hyFc exhibited a mean peak concentration at around 17hours and a rapid elimination with a half-life of 12.3hours. Peak concentration and area under the curve of TRA were higher than those of rhIL-7-hyFc. Tissue distribution analysis showed an elevated TRA concentrations in lymph nodes, kidneys, and spleen, indicating rhIL-7-hyFc's affinity for these organs. The study also simulated the positions of 14C labeling in rhIL-7-hyFc, identifying specific residues in the fragment of rhIL-7 portion, and provided the explanation of distinct analytes targeted by each method. Combining ELISA and AMS provided advantages by offering sensitivity and specificity for quantification as well as enabling the identification of analyte forms. The integrated use of ELISA and AMS offers valuable insights for the development and optimization of ABT.

Biomass conversion and radiocaesium (Rad-Cs) leaching behaviors of radioactive grass in anaerobic wet fermentation systems: Effects of pre-treatments

Persistent concerns regarding environmental hazards arise from the difficulty in disposing of radioactive plant-based wastes originating from the nuclear accident at the Fukushima Daiichi Nuclear Power Plant (FNPP) in Japan in 2011. In this study, three anaerobic digestion (AD) strategies were proposed: Sole anaerobic wet fermentation, and wet fermentations with either alkaline-heat or ultrasonic pre-treatment, which were employed for long-term anaerobic treatment of a genuine radioactive grass stemming from the FNPP accident. The objectives of this work are to investigate the effects of pre-treatments on biomass conversion efficiency and to gain insight into the leaching behavior of radiocaesium (Rad-Cs) within AD processes. Experimental results indicate that by introducing alkaline-heat and ultrasonic pre-treatments to AD systems, the removal efficiencies of total solids (TS) from the raw grass increased by 60.8 % and 42.5 %, respectively, compared to sole wet fermentation. Pre-treatments have been shown to enhance the stability of AD systems, both in terms of enhancing methane production and mitigating pH fluctuations triggered by the accumulation of organic acids. Remarkably, even though the Rad-Cs leaching rate was highest when the AD system was fed with the alkaline-heat pre-treated grass, it remained unsatisfactory at only 5.77 %. We inadvertently isolated a soil-like component from the raw grass, and analyzed both its proportion in the raw grass and the radioactivity intensity. The results indicate that although the soil constituted only 9.51 % TS of the raw grass, it accounted for a significant 81.35 % of the total radioactivity. The soil, which has a pronounced affinity for ionic Cs, being mixed into the raw grass, was identified as the primary factor limiting the leaching efficiency of Rad-Cs throughout both the pre-treatment and wet fermentation phases.

Pharmacokinetics, Disposition, and Biotransformation of [14C]Lenacapavir, a Novel, First-in-Class, Selective Inhibitor of HIV-1 Capsid Function, in Healthy Participants Following a Single Intravenous Infusion.

Lenacapavir (LEN) is a novel, first-in-class, multistage, selective inhibitor of human immunodeficiency virus type 1 (HIV-1) capsid function recently approved for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection. The purpose of this multicohort study was to evaluate the pharmacokinetics, metabolism, excretion, safety, and tolerability of LEN following a single intravenous (IV) infusion of 10 mg LEN or 20 mg [14C]LEN in healthy participants. Twenty-one healthy adult participants were enrolled into the study and received either a single IV dose of 10 mg LEN (n = 8 active, n = 3 placebo; cohort 1) or a single IV dose of 20 mg [14C]LEN containing 200 µCi (n = 10; cohort 2). Blood, urine, and feces samples (when applicable) were collected after dosing, and radioactivity (cohort 2) was assessed using liquid scintillation counting in both plasma and excreta. LEN in plasma was quantified by liquid chromatography (LC) tandem mass spectroscopy (MS/MS) method bioanalysis. Metabolite profiling in plasma and excreta were performed using LC-fraction collect (FC)-high-resolution MS and LC-FC-accelerator mass spectrometry in plasma. Between the 10 mg and 20 mg doses of LEN, the observed plasma exposure of LEN doubled, while the elimination half-life was similar. Following administration of 20 mg [14C]LEN (200 µCi), the mean cumulative recovery of [14C] radioactivity was 75.9% and 0.24% from feces and urine, respectively. The mean whole [14C] blood-to-plasma concentration ratio was 0.5-0.7, which showed a low distribution of LEN to red blood cells. Intact LEN was the predominant circulating species in plasma (representing 68.8% of circulating radioactivity), and no single metabolite contributed to >10% of total radioactivity exposure through 1176 h postdose. Similarly, intact LEN was the most abundant component (32.9% of administered dose; 75.9% of recovered dose) measured in feces, with metabolites accounting for trace amounts. These results suggest metabolism of LEN is not a primary pathway of elimination. Of the metabolites observed in the feces, the three most abundant metabolites were direct phase 2 conjugates (glucuronide, hexose, and pentose conjugates), with additional metabolites formed to a lesser extent via other pathways. The administered LEN IV doses were generally safe and well-tolerated across participants in this study. The results of this mass balance study indicated that LEN was majorly eliminated as intact LEN via the feces. The renal pathway played a minor role in LEN elimination (0.24%). In addition, no major circulating metabolites in plasma or feces were found, indicating minimal metabolism of LEN.

Mass Balance and Metabolite Profile after Single and Multiple Oral Doses of Pritelivir in Healthy Subjects.

Pritelivir is a helicase-primase inhibitor active against HSV. Two human mass balance trials (a multiple-dose trial and a single-dose trial) were performed to characterize the absorption, distribution, metabolism, and excretion of 100mg oral pritelivir combined with a single microdose of 14C-pritelivir. Blood, urine, and feces samples were collected up to 26 days postdose. The plasma half-life of pritelivir was 63-67 hours. Overall, 92% and 66% of the administered dose was recovered in the multiple and single dose trials, respectively. The low recovery after the single dose (66%) was most likely related to the formulation used. The major metabolic pathway was amide hydrolysis leading to amino thiazole sulfonamide (ATS) and pyridinyl phenyl acetic acid (PPA). In plasma, pritelivir, ATS, PPA, and PPA-acyl glucuronide accounted for 40.6%, 9.4%, 5.1%, and 0.2% of total radioactivity. More than 90% of drug-related material was eliminated 624 hours postdose. The majority was excreted in urine (75% and 77%), followed by feces (16% and 23%). The main components in urine were PPA-acyl glucuronide (and its isomers), ATS, and its N-demethylated isomers. Only minor metabolites were observed in feces. In conclusion, the major metabolic pathways of pritelivir have been identified with the primary excretion route being renal.

Radioactivation effects of titanium caused by clinical proton beam: a simulation study

Objective. In proton beam therapy (PBT), metals in the patient body perturb the dose distribution, and their radioactivation may affect the dose distribution around the metal; however, the radioactivation effect has been not clarified with PBT. In this study, we aimed to evaluate the radioactivation effect of metal depending on proton energies and secondary neutrons with a clinical proton beam using a Monte Carlo (MC) simulation. Approach. The radionuclides produced from a titanium alloy (Ti-6Al-4V) and their radioactivity were calculated using a 210-MeV passive scattering proton beam with a 60-mm Spread-out Bragg Peak, and the deposited doses caused by the radioactivation were computed using the MC simulation. The position of metal was changed according to the proton mean energy in water. To assess neutron effects on the radioactivation, we calculated the radioactivation in following three situations: (i) full MC simulation with neutrons, (ii) simulation without secondary neutrons generated from the beamline components, and (iii) simulation without any secondary neutrons. Main results. Immediately after the irradiation, the radionuclide with the largest activity was Sc-45 m (half-life of 318 ms) regardless of the proton energy and the presence of neutrons. Total radioactivity tended to increase according to the proton energy. The accumulated dose for 24 h caused by the metal activation showed an increasing trend with the proton energy, with a maximum increase rate of 0.045% to the prescribed dose. The accumulated dose at a distance of 10 mm from the metal was lower than 1/10 of that at a distance of 1 mm. Significance. The radioactivation effect of the titanium was comprehensively evaluated in the clinical passive scattering proton beam. We expect that radioactivation effects on the clinical dose distribution would be small. We consider that these results will help the clinical handling of high-Z metals in PBT.

Tritium labeling vancomycin and studying its adsorption on nanodiamonds

Procedure of tritium labeling vancomycin using tritium thermal activation method has been developed. The influence of target mass on the specific and total radioactivity was revealed. [3H]vancomycin was used for studying its equilibrium adsorption on nanodiamonds as well as its number that tightly bonded with surface and didn’t remove with water. It was found that adsorption from aqueous solution results in tightly bonded vancomycin with nanodiamonds that didn’t removed with water. Application of 0.028 M phosphate buffer (pH 6.7 and 2.7) leads to the equilibrium adsorption growth as much as one and a half times, while vancomycin number in the adsorption complex with nanodiamonds after washing with water was significantly reduced. Such behavior of vancomycin is due to the presence of phosphate-ions that contribute to vancomycin adsorption, but are removed during washing with water. Molecular mechanics simulation allows us to suggest the formation of multiple hydrogen bonds for formation of a durable adsorption complex of vancomycin with nanodiamonds.

Mass Balance and Metabolic Pathways of Eliapixant, a P2X3 Receptor Antagonist, in Healthy Male Volunteers.

Overactive adenosine triphosphate signaling via P2X3 homotrimeric receptors is implicated in multiple conditions. To fully understand the metabolism and elimination pathways of eliapixant, a study was conducted to assess the pharmacokinetics, mass balance, and routes of excretion of a single oral dose of the selective P2X3 receptor antagonist eliapixant, in addition to an invitro characterization. In this single-center open-label non-randomized non-placebo-controlled phase I study, healthy male subjects (n=6) received a single dose of 50mg eliapixant blended with 3.7MBq [14C]eliapixant as a PEG 400-based oral solution. Total radioactivity and metabolites excreted in urine and feces, and pharmacokinetics of total radioactivity, eliapixant, and metabolites in plasma were assessed via liquid scintillation counting and high-performance liquid chromatography-based methods coupled to radiometric and mass spectrometric detection. Metabolite profiles of eliapixant in human invitro systems and metabolizing enzymes were also investigated. After administration as an oral solution, eliapixant was rapidly absorbed, reaching maximum plasma concentrations within 2h. Eliapixant was eliminated from plasma with a mean terminal half-life of 48.3h. Unchanged eliapixant was the predominant component in plasma (72.6% of total radioactivity area under the curve). The remaining percentage of drug-related components in plasma probably represented the sum of many metabolites, detected in trace amounts. Mean recovery of total radioactivity was 97.9% of the administered dose (94.3-99.4%) within 14 days, with 86.3% (84.8-88.1%) excreted via feces and 11.6% (9.5-13.1%) via urine. Excretion of parent drug was minimal in feces (0.7% of dose) and urine (≈0.5%). In feces, metabolites formed by oxidation represented > 90% of excreted total radioactivity. The metabolites detected in the invitro experiments were similar to those identified invivo. Complete recovery of administered eliapixant-related radioactivity was observed in healthy male subjects with predominant excretion via feces. Eliapixant was almost exclusively cleared by oxidative biotransformation (>90% of dose), with major involvement of cytochrome P450 3A4. Excretion of parent drug was of minor importance (~1% of dose). ClinicalTrials.gov: NCT04487431 (registered 27 July 2020)/EudraCT number: 2020-000519-54 (registered 3 February 2020), NCT02817100 (registered 26 June 2016), NCT03310645 (registered 16 October 2017).

In vitro and in vivo pharmacokinetics, disposition, and drug-drug interaction potential of tinengotinib (TT-00420), a promising investigational drug for treatment of cholangiocarcinoma and other solid tumors

Early-stage clinical evaluation of tinengotinib (TT-00420) demonstrated encouraging preliminary efficacies in multiple types of refractory cancers, including fibroblast growth factor receptors (FGFR) inhibitors relapsed cholangiocarcinoma (CCA), castrate-resistant prostate cancer (CRPC), and HR+/HER2- breast cancer and triple negative breast cancer (TNBC). To further evaluate drug-like properties of the drug candidate, it is imperative to understand its metabolism and pharmacokinetic properties. This manuscript presented the investigation results of in vitro permeability, plasma protein binding, metabolic stability, metabolite identification, and drug-drug interaction of tinengotinib. Preclinical ADME (absorption, distribution, excretion, and metabolism) studies in rats and dogs was also conducted using a radioactive labeled tinengotinib, [14C]tinengotinib. Tinengotinib was found to have high permeability and high plasma protein binding and equally distributed between blood and plasma. There were no unique metabolites in human liver microsomes and tinengotinib showed moderate hepatic clearance. Tinengotinib is neither a potential inhibitor nor an inducer of P450 enzymes at clinically relevant concentrations, and unlikely to cause drug-drug interactions when used in combination with other drugs mediated by a key transporter, either as victim or perpetrator. Taken together, tinengotinib demonstrated a minimal risk of clinically relevant drug-drug interactions. Tinengotinib showed good oral bioavailability and dose-dependent exposures in both rat and dog after oral administration. The total radioactivity was largely distributed in the gastrointestinal system and liver, and tinengotinib could not easily pass through the blood-brain barrier. The major drug-related component in rat and dog plasma was unchanged drug (>89 %) with primary route of elimination via feces (>93 % of the dose) and minor via renal excretion (<4 % of the dose). Tinengotinib metabolism is mediated largely by CYP3A4, with minor contributions from CYP2D6 and CYP2C8. Major metabolic pathways include oxidation, oxidative cleavage of the morpholine ring, glucuronide and glutathione conjugations. The overall preclinical pharmacokinetics profile supported the selection and development of tinengotinib as a clinical candidate.

Important role of turbulence on the distribution of particle radioactivity in the nuclear explosions

The distribution of particle radioactivity is one of the most important source items of radioactive fallout prediction model for nuclear explosion. For radioactive particles with the diameter larger than 0.5 μm, the influence of turbulent coagulation cannot be ignored. However, few scholars have considered the role of turbulence in the study of the distribution of particle radioactivity. The General Dynamic Equation (GDE), which is solved using the Multi-Monte Carlo method, is used in this study to establish a new model of the distribution of particle radioactivity that takes the impact of turbulent coagulation into account. The results present that the surface and volume distributions of particle radioactivity are closer to those of the Defense Land Fallout Interpretative Code (DELFIC) model, and the relative error of the surface (volume) distribution reduces from 1.243 (0.687) to 0.945 (0.284) when compared to the previous model that simply takes Brownian coagulation into account. The geometric median diameter of total particle radioactivity increases as the solidification temperature increases and as the particle size range increases when considering the influence of various geological conditions. When considering the effects of turbulent coagulation, the differences in the particle radioactivity produced under different geological conditions are smaller than those only considering the Brownian coagulation. This study highlights the importance of turbulent coagulation on the distribution of particle radioactivity in the nuclear explosions.

Dynamic blood flow imaging with 99mTc-hydroxymethylene diphosphonate as a therapeutic response marker in patients with Raynaud's phenomenon.

We evaluated the predictive value of dynamic blood flow scintigraphy with 99mTc-HDP (hydroxymethylene diphosphonate) for therapeutic response in patients with Raynaud's phenomenon (RP). Eighty patients who underwent dynamic blood flow scintigraphy using the one-hand chilling method were enrolled. We analyzed the quantitative variables as the ratio of chilled fingers to ambient fingers (CAfinger), that of the chilled hand to ambient hand (CAhand), and that of chilled fingers to ambient palm (FPR) (CAFPR) at 15 and 30s after 99mTc-HDP bolus injection. Total cumulative radioactivity counts for 180s were obtained. We evaluated the clinical utility of these quantitative parameters with other clinical variables, including RP severity, therapeutic compliance, types of RP, and scintigraphic interpretation of findings in patients with RP. Fifty-two patients showed poor therapeutic response. There were significant differences between good- and poor-therapeutic responder groups in RP intensity (p = 0.003), CAfinger15s (p = 0.008), CAfinger30s (p = 0.002), CAfinger180s (p = 0.011), CAhand15s (p = 0.008), CAhand30s (p = 0.007), CAhand180s (p = 0.017), CAFPR30s (p = 0.004), and CAFPR180s (p = 0.002). After multivariate logistic regression analysis, only CAfinger30s (p = 0.002) had an independent predictive value of the therapeutic response. 99mTc-HDP dynamic blood flow scintigraphy could be helpful in predicting the therapeutic response in patients with RP.

Pharmacokinetics, Mass Balance, Tissue Distribution and Metabolism of [14C]101BHG-D01, a Novel Muscarinic Receptor Antagonist, in Rats.

101BHG-D01, a novel long-acting and selective muscarinic receptor antagonist for the treatment of chronic obstructive pulmonary disease (COPD), is undergoing Phase Ib clinical trial in patients and has shown its potential efficacy. Its preparation method and medical use thereof have been patented in the United States (Patent No.US9751875B2). In this study, the pharmacokinetics, mass balance, tissue distribution and metabolism of radioactive 101BHG-D01 were investigated in rats after an intravenous dose of 1 mg/kg [14C]101BHG-D01 (100 μCi/kg). Radioactivity in rat plasma, urine, feces, and tissues was measured by liquid scintillation counting (LSC), and metabolite profiling and identification were conducted by UHPLC-β-RAM and UHPLC-Q-Exactive Plus MS. The total radioactivity of the study drug in rat plasma rapidly declined with an average terminal elimination half-life of 0.35 h. The radioactivity in most tissues reached the maximum concentration at 0.25 h post-- dosing. The radioactivity mainly concentrated in the kidney and pancreas. The drug-related substances tended to be distributed into the blood cells in the circulation. At 168 h post dosing, the mean recovery of the total radioactivity in urine and feces was 78.82%. Fecal excretion was the major excretion route, accounting for approximately 61% of the radioactive dose. The study drug was metabolized extensively, and a total of 17 metabolites were identified in rat plasma, urine, and feces. The major metabolic pathways involved oxidation, oxidation and dehydrogenation, and O-dephenylation. In conclusion, the study results are useful for better understanding the pharmacokinetic profiles of 101BHG-D01 and provide a robust foundation for subsequent clinical studies.

Absorption, metabolism and excretion of 14C-emvododstat following repeat daily oral dose administration in human volunteers using a combination of microtracer radioactivity and high radioactivity doses.

Emvododstat is a potent inhibitor of dihydroorotate dehydrogenase and is now in clinical development for the treatment of COVID-19 and acute myeloid leukemia. Since the metabolism and pharmacokinetics of emvododstat in humans is time‑dependent, a repeat dose study design using a combination of microtracer radioactivity and high radioactivity doses was employed to evaluate the metabolism and excretion of emvododstat near steady state. Seven healthy male subjects each received 16 mg/0.3 µCi 14C-emvododstat daily oral doses for 6 days followed by a 16 mg/100 µCi high radioactivity oral dose on Day 7. Following the last 16 mg/0.3 µCi 14C‑emvododstat dose on Day 6, total radioactivity in plasma peaked at 6 h post-dose. Following a high radioactivity oral dose (16 mg/100 µCi) of 14C-emvododstat on Day 7, both whole blood and plasma radioactivity peaked at 6 h, rapidly declined from 6 h to 36 h post-dose, and decreased slowly thereafter with measurable radioactivity at 240 h post-dose. The mean cumulative recovery of the administered dose was 6.0% in urine and 19.9% in feces by 240 h post-dose, and the mean extrapolated recovery to infinity was 37.3% in urine and 56.6% in feces. Similar metabolite profiles were observed after repeat daily microtracer radioactivity oral dosing on Day 6 and after a high radioactivity oral dose on Day 7. Emvododstat was the most abundant circulating component, M443 and O-desmethyl emvododstat glucuronide were the major circulating metabolites; M474 was the most abundant metabolite in urine, while O‑desmethyl emvododstat was the most abundant metabolite in feces. Significance Statement This study provides a complete set of the absorption, metabolism and excretion data of emvododstat, a potent inhibitor of dihydroorotate dehydrogenase, at close to steady state in healthy human subjects. Resolution of challenges due to slow metabolism and elimination of a lipophilic compound highlighted in this study can be achieved by repeat daily microtracer radioactivity oral dosing followed by a high radioactivity oral dosing at therapeutically relevant doses.

Pharmacokinetics, Mass Balance and Metabolism of [14C]HSK21542, a Novel Kappa Opioid Receptor Agonist, inHumans.

HSK21542, a synthetic short-chain polypeptide, is a selective peripheral kappa opioid receptor (KOR) agonist. In this single-centre, non-randomized, open-label study, the pharmacokinetics, mass balance, metabolism and excretion ofHSK21542 were investigated. A single intravenous dose of 2μg/0.212μCi/kg [14C]HSK21542 was administered to sixhealthy male subjects. Samples of blood, urine and faeces were collected for quantitative determination of total radioactivity and unchangedHSK21542, and identification of metabolites. The mean total recovery was 81.89% of the radiolabelled dose over 240h post-dose, with 35.60% and 46.30% excreted in faeces and urine, respectively. The mean maximum concentration (Cmax), thehalf-life (t1/2) and the area under the concentration-time curve (AUC0-t) of total radioactivity (TRA) in plasma were 20.4±4.16ngEq./g, 1.93±0.322h and 21.8±2.93h·ngEq./g, respectively, while the Cmax, t1/2 and the AUC0-t of unchangedHSK21542 were 18.3±3.36ng/mL, 1.66±0.185h and 18.4±2.24h·ng/mL, respectively. The blood-to-plasma ratios of TRA at several times ranged from 0.46 to 0.54. [14C]HSK21542 was detected as the main circulating substance in plasma, accounting for 92.17% of the AUC of TRA. The unchanged parent compound was the only major radioactive chemical in urine (100.00% of TRA) and faeces (93.53% of TRA). Metabolites were veryminor components. HSK21542 was barely metabolized in vivo and mainly excreted with unchangedHSK21542 as its main circulating component in plasma. It was speculated that renal excretion was the principal excretion pathway, and faecal excretion was the secondary pathway. NCT05835934.

Mineralization of Few-Layer Graphene Made It Bioavailable in Chlamydomonas reinhardtii.

Numerous studies have emphasized the toxicity of graphene-based nanomaterials to algae, however, the fundamental behavior and processes of graphene in biological hosts, including its transportation, metabolization, and bioavailability, are still not well understood. As photosynthetic organisms, algae are key contributors to carbon fixation and may play an important role in the fate of graphene. This study investigated the biological fate of 14C-labeled few-layer graphene (14C-FLG) in Chlamydomonas reinhardtii (C.reinhardtii). The results showed that 14C-FLG was taken up by C.reinhardtii and then translocated into its chloroplast. Metabolomic analysis revealed that 14C-FLG altered the metabolic profiles (including sugar metabolism, fatty acid, and tricarboxylic acid cycle) of C.reinhardtii, which promoted the photosynthesis of C.reinhardtii and then enhanced their growth. More importantly, the internalized 14C-FLG was metabolized into 14CO2, which was then used to participate in the metabolic processes required for life. Approximately 61.63%, 25.31%, and 13.06% of the total radioactivity (from 14CO2) was detected in carbohydrates, lipids, and proteins of algae, respectively. Overall, these results reveal the role of algae in the fate of graphene and highlight the potential of available graphene in bringing biological effects to algae, which helps to better assess the environmental risks of graphene.

Study of the mass balance, biotransformation and safety of [14C]SHR8554, a novel μ-opioid receptor injection, in healthy Chinese subjects.

Background: SHR8554 is a novel μ-opioid receptor-biased agonist. It has analgesic effects by selectively activating the G protein-coupled pathway. Additionally, it can weakly activate the ß-arrestin-2 pathway, resulting in a limited number of side effects, such as gastrointestinal inhibition. Previous studies have shown that SHR8554 has good analgesic effects, safety and tolerability, but the pharmacokinetic characteristics of SHR8554 in humans have not been reported. This study was designed to investigate the pharmacokinetics and safety of SHR8554 in healthy Chinese male subjects. Methods: A single 1mg/41.3μCi intravenous dose of [14C]SHR8554 was administered to six healthy male subjects. Blood, urine and faecal samples were collected at continuous time points to analyse SHR8554 parent drug levels and their metabolites. The total radioactivity in blood, plasma, urine and faeces was detected by using a liquid scintillation counter. The dynamic changes of SHR8554 and its metabolite concentration were by liquid chromatography-tandem mass spectrometry (LC/MS), and then pharmacokinetic analysis. The safety of the drug on the subjects was also observed after a single intravenous injection. Results: The total recovery of radioactivity in urine and faeces was 99.68% ± 0.79% in 216h, including 76.22% ± 1.12% in urine and 23.46% ± 1.36% in faeces. Seventeen major metabolites in blood, urine and faeces were analysed and identified. The main metabolic pathways of SHR8554 in the human body involve 1) N-dealkylation; 2) O-deethylation; 3) mono-oxidation; 4) glucuronidation, etc. The primary mechanism of SHR8554 clearance in the human body is through urinary excretion, primarily in its parent drug and metabolite forms. The drug has good safety, and no serious adverse effects were observed. Conclusion: SHR8554 showed favourable pharmacokinetic characteristics and safety profiles in this study. SHR8554 is extensively metabolized in human body. The main metabolic pathways include N-dealkylation and O-deethylation, as well as mono-oxidation and glucuronidation. The main excretion route of SHR8554 and its metabolites is through urine. Clinical Trial Registration: http://www.chinadrugtrials.org.cn/, identifier CTR20220450.