Route Of Elimination Research Articles

Kinetic time courses of inhaled silver nanoparticles in rats.

Silver nanoparticles (Ag NPs) are priority substances closely monitored by health and safety agencies. Despite their extensive use, some aspects of their toxicokinetics remain to be documented, in particular following inhalation, the predominant route of exposure in the workplace. A same experimental protocol and exposure conditions were reproduced two times (experiments E1 and E2) to document the kinetic time courses of inhaled Ag NPs. Rats were exposed nose-only to 20nm Ag NPs during 6h at a target concentration of 15mg/m3 (E1: 218,341 ± 85,512 particles/cm3; E2, 154,099 ± 5728 particles/cm3). The generated aerosol showed a uniform size distribution of nanoparticle agglomerates with a geometric mean diameter ± SD of 79.1 ± 1.88nm in E1 and 92.47 ± 2.19nm in E2. The time courses of elemental silver in the lungs, blood, tissues and excreta were determined over 14days following the onset of inhalation. Excretion profiles revealed that feces were the dominant excretion route and represented on average (± SD) 5.1 ± 3.4% (E1) and 3.3 ± 2.5% (E2) of the total inhaled exposure dose. The pulmonary kinetic profile was similar in E1 and E2; the highest percentages of the inhaled dose were observed between the end of the 6-h inhalation up to 6-h following the end of exposure, and reached 1.9 ± 1.2% in E1 and 2.5 ± 1.6% in E2. Ag elements found in the GIT followed the trend observed in lungs, with a peak observed at the end of the 6-h inhalation exposure and representing 6.4 ± 4.9% of inhaled dose, confirming a certain ingestion of Ag NPs from the upper respiratory tract. Analysis of the temporal profile of Ag elements in the liver showed two distinct patterns: (i) progressive increase in values with peak at the end of the 6-h inhalation period followed by a progressive decrease; (ii) second increase in values starting at 72h post-exposure with maximum levels at 168-h followed by a progressive decrease. The temporal profiles of Ag elements in lymphatic nodes, olfactory bulbs, kidneys and spleen also followed a pattern similar to that of the liver. However, concentrations in blood and extrapulmonary organs were much lower than lung concentrations. Overall, results show that only a small percentage of the inhaled dose reached the lungs-most of the dose likely remained in the upper respiratory tract. The kinetic time courses in the gastrointestinal tract and liver showed that part of the inhaled Ag NPs was ingested; lung, blood and extrapulmonary organ profiles also suggest that a small fraction of inhaled Ag NPs progressively reached the systemic circulation by a direct translocation from the respiratory tract.

The metabolism and excretion of the dipeptidyl peptidase 4 inhibitor [14C] cetagliptin in healthy volunteers

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.

Targeting HER2 Expressing Tumors with a Potent Drug Conjugate Based on an Albumin Binding Domain-Derived Affinity Protein.

Albumin binding domain derived affinity proteins (ADAPTs) are a class of small and folded engineered scaffold proteins that holds great promise for targeting cancer tumors. Here, we have extended the in vivo half-life of an ADAPT, targeting the human epidermal growth factor receptor 2 (HER2) by fusion with an albumin binding domain (ABD), and armed it with the highly cytotoxic payload mertansine (DM1) for an investigation of its properties in vitro and in vivo. The resulting drug conjugate, ADAPT6-ABD-mcDM1, retained binding to its intended targets, namely HER2 and serum albumins. Further, it was able to specifically bind to cells with high HER2 expression, get internalized, and showed potent toxicity, with IC50 values ranging from 5 to 80 nM. Conversely, no toxic effect was found for cells with low HER2 expression. In vivo, ADAPT6-ABD-mcDM1, radiolabeled with 99mTc, was characterized by low uptake in most normal organs, and the main excretion route was shown to be through the kidneys. The tumor uptake was 5.5% ID/g after 24 h, which was higher than the uptake in all normal organs at this time point except for the kidneys. The uptake in the tumors was blockable by pre-injection of an excess of the monoclonal antibody trastuzumab (having an overlapping epitope on the HER2 receptor). In conclusion, half-life extended drug conjugates based on the ADAPT platform of affinity proteins holds promise for further development towards targeted cancer therapy.

Patients With Cirrhosis Have Elevated Bone Turnover but Normal Hepatic Production of Osteoprotegerin.

Severe osteodystrophy is common in patients with liver dysfunction. Markers of bone metabolism may help in early diagnosis of osteodystrophy and in understanding underlying pathophysiological mechanisms. To elucidate changes in bone metabolism associated with cirrhosis and to determine the route of elimination for the markers. Case-control study at a public university hospital. Fifty-nine patients with cirrhosis (47 alcoholic and 12 nonalcoholic cirrhosis) and 20 controls were included. Participants underwent catheterization of the femoral artery, and the hepatic, renal, and femoral veins with collection of blood from all 4 sites. Regional arteriovenous differences in concentrations of bone metabolism markers were determined: procollagen of type I collagen propeptide (PINP), C-terminal cross-linking telopeptide of type I collagen (CTX), osteocalcin, tartrate-resistant acid phosphatase isoform 5b (TRAcP5b), osteoprotegerin (OPG), and sclerostin and correlated with degree of disease (Child-Pugh classification). PINP concentration was higher (median: 87.9 µg/L) in patients with cirrhosis than in controls (52.6 µg/L) (P = .001), while hepatic extraction was lower (4.3% vs 14.5%) (P < .001). Both CTX and TRAcP5b were higher in patients with cirrhosis (340 ng/L and 3.20 U/L) than in controls (215 ng/L and 1.60 U/L) (P < .001 and P < .0001). Hepatic sclerostin extraction was lower in patients with cirrhosis (14.6%) than in controls (28.7%) (P < .0001). In both groups OPG showed a hepatic release rate (production) of 6%. Patients with cirrhosis have increased bone resorption, but unaltered bone formation. Sclerostin is eliminated through the liver while OPG is produced in the liver. Bone markers may prove useful in evaluating bone turnover in patients with cirrhosis.

Pharmacokinetics of Azalomycin F, a Natural Macrolide Produced by Streptomycete Strains, in Rats.

As antimicrobial resistance has been increasing, new antimicrobial agents are desperately needed. Azalomycin F, a natural polyhydroxy macrolide, presents remarkable antimicrobial activities. To investigate its pharmacokinetic characteristics in rats, the concentrations of azalomycin F contained in biological samples, in vitro, were determined using a validated high-performance liquid chromatography–ultraviolet (HPLC-UV) method, and, in vivo, samples were assayed by an ultra-high performance liquid chromatography–tandem mass spectrometric (UPLC–MS/MS) method. Based on these methods, the pharmacokinetics of azalomycin F were first investigated. Its plasma concentration-time courses and pharmacokinetic parameters in rats were obtained by a non-compartment model for oral (26.4 mg/kg) and intravenous (2.2 mg/kg) administrations. The results indicate that the oral absolute bioavailability of azalomycin F is very low (2.39 ± 1.28%). From combinational analyses of these pharmacokinetic parameters, and of the results of the in-vitro absorption and metabolism experiments, we conclude that azalomycin F is absorbed relatively slowly and with difficulty by the intestinal tract, and subsequently can be rapidly distributed into the tissues and/or intracellular f of rats. Azalomycin F is stable in plasma, whole blood, and the liver, and presents plasma protein binding ratios of more than 90%. Moreover, one of the major elimination routes of azalomycin F is its excretion through bile and feces. Together, the above indicate that azalomycin F is suitable for administration by intravenous injection when used for systemic diseases, while, by oral administration, it can be used in the treatment of diseases of the gastrointestinal tract.

Molecular Properties of Drugs Handled by Kidney OATs and Liver OATPs Revealed by Chemoinformatics and Machine Learning: Implications for Kidney and Liver Disease.

In patients with liver or kidney disease, it is especially important to consider the routes of metabolism and elimination of small-molecule pharmaceuticals. Once in the blood, numerous drugs are taken up by the liver for metabolism and/or biliary elimination, or by the kidney for renal elimination. Many common drugs are organic anions. The major liver uptake transporters for organic anion drugs are organic anion transporter polypeptides (OATP1B1 or SLCO1B1; OATP1B3 or SLCO1B3), whereas in the kidney they are organic anion transporters (OAT1 or SLC22A6; OAT3 or SLC22A8). Since these particular OATPs are overwhelmingly found in the liver but not the kidney, and these OATs are overwhelmingly found in the kidney but not liver, it is possible to use chemoinformatics, machine learning (ML) and deep learning to analyze liver OATP-transported drugs versus kidney OAT-transported drugs. Our analysis of >30 quantitative physicochemical properties of OATP- and OAT-interacting drugs revealed eight properties that in combination, indicate a high propensity for interaction with “liver” transporters versus “kidney” ones based on machine learning (e.g., random forest, k-nearest neighbors) and deep-learning classification algorithms. Liver OATPs preferred drugs with greater hydrophobicity, higher complexity, and more ringed structures whereas kidney OATs preferred more polar drugs with more carboxyl groups. The results provide a strong molecular basis for tissue-specific targeting strategies, understanding drug–drug interactions as well as drug–metabolite interactions, and suggest a strategy for how drugs with comparable efficacy might be chosen in chronic liver or kidney disease (CKD) to minimize toxicity.

Development and preclinical evaluation of novel fluorinated ammonium salts for PET myocardial perfusion imaging

We previously presented the radiolabeled ammonium salt [11C]-dimethyl diphenylammonium trifluoromethanesulfonate ([11C]DMDPA) as a potential novel PET-MPI agent. The current study aimed to increase the clinical applicability of PET-MPI by designing and synthesizing fluorinated ammonium salt derivatives. Four fluorinated DMDPA derivatives and two quinolinium salt analogs were radiolabeled. The dynamic distribution in vivo, following injection of each derivative into male SD rats, was evaluated using small-animal dedicated PET/CT. Organ uptake after injection of [18F]fluoroethylquinolinium acetate ([18F]FEtQ) was examined ex vivo. Four fluorinated DMDPA derivatives were synthesized, two were labeled with fluorine-18: [18F]fluoroethyl-methyldiphenylammonium trifluoromethanesulfonate ([18F]FEMDPA) and [18F]fluorobuthyl-methyldiphenylammonium trifluoromethanesulfonate ([18F]FBMDPA). The other two were labeled using carbon-11: [11C]methyl-(3-fluorophenyl)-methylphenylammonium trifluoromethanesulfonate ([11C]3-F-DMDPA) and [11C]methyl-(4-fluorophenyl)-methylphenylammonium trifluoromethanesulfonate ([11C]4-F-DMDPA). All four DMDPA derivatives exhibited significantly lower heart/liver radioactivity uptake ratios (0.6, 0.4, 0.7 and 0.6, respectively) compared to that of [11C]DMDPA (1.2). Conversely, the two radiolabeled quinolinium salt derivatives, [11C]methylquinolinium iodide ([11C]MeQ) and [18F]FEtQ demonstrated improved heart/liver ratios (2.0 and 1.3, respectively) with clear visualization of the left ventricle myocardium. Renal clearance was the major route of elimination. Among the fluorinated quaternary ammonium salts tested, [18F]FEtQ yielded the best images. Further studies are in progress to elucidate the underlying mechanism of its cardiac uptake.

Absorption, metabolism and excretion of once-weekly somapacitan, a long-acting growth hormone derivative, after single subcutaneous dosing in human subjects

Somapacitan is a reversible albumin-binding growth hormone (GH) derivative in clinical development for once-weekly administration in patients with adult GH deficiency (AGHD) and children with GH deficiency (GHD). To date, the use of somapacitan in AGHD or severe AGHD has been approved in the USA and Japan, respectively. This study (ClinicalTrials.gov, NCT02962440) investigated the absorption, metabolism and excretion, as well as the pharmacokinetics (PK), of tritium-labelled somapacitan ([3H]-somapacitan). Seven healthy males received a single subcutaneous dose of 6 mg somapacitan containing [3H]-somapacitan 20 MBq. Blood, serum, plasma, urine, faeces, and expired air were collected for radioactivity assessment. Metabolites were identified and quantified in plasma and urine collected. The PK of plasma components were determined, and the radioactive peaks of the most abundant plasma metabolites and urine metabolites were selected for analysis. Twenty-eight days after dosing, 94.0% of the administered dose was recovered as [3H]-somapacitan-related material, most of which was excreted in urine (80.9%); 12.9% was excreted in faeces, and an insignificant amount (0.2%) was exhaled in expired air. PK properties of [3H]-somapacitan-related material appeared to be consistent across plasma, serum and blood. Three abundant plasma metabolites (P1, M1 and M1B) and two abundant urine metabolites (M4 and M5) were identified. The total exposure of intact somapacitan accounted for 59% of the total exposure of all somapacitan-related material, P1 accounted for 21% and M1 plus M1B accounted for 12%. M4 and M5 were the most abundant urine metabolites and accounted for 37% and 8% of the dosed [3H]-somapacitan radioactivity, respectively. No intact somapacitan was found in excreta. Two subjects had six adverse events (AEs); all were mild in severity and unlikely to be related to trial product. The majority of dosed [3H]-somapacitan (94%) was recovered as excreted metabolites. Urine was the major route for excretion of somapacitan metabolites, followed by faeces, and exhalation in expired air was negligible. The low molecular weights of identified urine metabolites demonstrate that somapacitan was extensively degraded to small residual fragments that were excreted (fully biodegradable). The extensive metabolic degradation and full elimination of metabolites in excreta were the major clearance pathways of somapacitan and the key elements in its biological fate. A single dose of 6 mg somapacitan (containing [3H]-somapacitan) in healthy male subjects was well tolerated with no unexpected safety issues identified.

Preparation of zeolite A by inorganic complex precursor route for efficient elimination of heavy metal cations from aqueous solutions

In the present study, zeolite A was synthesized via inorganic complex precursor as an efficient novel route by using tris(acetylacetonato)aluminum(III), [Al(C5H7O2)3], and tris(acetylacetonato)silicon(IV) chloride hydrochloride, [Si(C5H7O2)3]Cl.HCl. The physicochemical properties of the zeolite A were characterized by FT-IR, XRD, SEM/EDX, BJH, and BET techniques. The performance of the synthesized zeolite A was evaluated for the elimination of heavy metal cations (Co2+, Cu2+, Zn2+, Cr3+ and Pb2+) from aqueous solutions. The results revealed that removal efficiencies of the synthesized zeolite A toward all investigated heavy metal cations were obtained to be more than 95% and the maximum removal efficiency was observed for Pb2+. The influence of parameters such as pH, contact time and adsorbent amount was surveyed on the removal efficiency of Pb2+ by the zeolite A. The most desirable conditions for Pb2+ removal was attained at pH 6.5, the zeolite amount of 0.5 g, 400 mgL−1 initial concentration of Pb2+ and the contact time of 30 min. The adsorption process followed second- order kinetics model and the pseudo-second-order adsorption rate constant (k 2) was obtained to be 4.32 × 10−4 g mg−1min−1.

177Lu-doxycycline as potential radiopharmaceutical: electrochemical characterization, radiolabeling, and biodistribution in tumor-bearing mice

Purpose Recent studies with doxycycline as adjuvant therapy to conventional chemotherapy have shown promising results in cancer therapy. The current study aimed to examine the capability of 177Lu-labeled tetracycline ligand, doxycycline hyclate, to use as an anticancer agent. Materials and methods Doxycycline was radiolabeled with beta-emitting radioisotope 177Lu. Complex formation and it interaction with DNA was investigated electrochemicaly. Binding of 177Lu-doxycycline to CT 26 cell line was done. Biodistribution of 177Lu-doxycycline was examined in healthy Wistar rats and in CT26 colon carcinoma tumor bearing mice by i.v. and i.p. administration, respectively. Results Doxycycline hyclate was successfully radiolabeled with 177Lu in high radiolabeling yield (>99%). The radiolabeled complex was stable in vitro in saline and human serum over 72 h. Non-radioactive Lu-doxycycline complex formation was demonstrated electrochemically as well. Intercalative interactions of the doxycycline and Lu-doxycycline with DNA were proved using simultaneously spectrophotometric and electrochemical methods. The binding of the radiolabeled complex with plasma proteins was 4.0 ± 0.4%. Partition coefficient showed the lipophilic nature of the complex similarly to free ligand. Binding curve demonstrates binding from 0.1 nM concentrations of 177Lu-doxycycline, with half-binding estimated ∼100 nM. Biodistribution studies of 177Lu-doxycycline in CT26 colon tumor bearing mice showed satisfactory accumulation rate in the tumor (2.88 ± 0.85% ID/g) 3 h after intraperitoneal injection. Both the hepatobiliary system and the urinary system were prominent as excretory routes of the radiolabeled complex. Conclusion Considering obtained results, 177Lu-doxycycline complex, due to its excellent electrochemical and biological characteristics, with emphasis on the binding ability to DNA via intercalative interaction as well as significant accumulation in the tumor, is suitable for further in vivo studies to investigate its potential use in cancer treatment.

Absorption, distribution, metabolism, and excretion of [14C]NBP (3-n-butylphthalide) in rats

3-n-Butylphthalide (NBP) has a considerable neuroprotective effect and is currently used for the treatment of ischemic stroke. NBP was launched on the market in 2004. However, information on its metabolism in humans and preclinical animal models is insufficient. Although the metabolism of unradiolabeled NBP in humans has been reported, the quantitative metabolite profile, blood-to-plasma radioactivity concentration ratio (B/P), and tissue distribution of this drug remain unclear. We evaluated the pharmacokinetics, tissue distribution, mass balance, and metabolism of NBP in rats after a single oral dose of 60 mg/kg (100 μCi/kg) [14C]NBP to understand the biotransformation of NBP comprehensively and to provide preclinical drug metabolism data prior to human mass balance studies with [14C]NBP in the near future. NBP absorption was rapid (Tmax = 0.75 h) and declined with a terminal half-life of 9.73 h. In rats, the B/P was 0.63 during the 48 h postdose period, indicating that drug-related substances did not tend to be distributed into blood cells. Tissue distribution was determined by using the oxidative combustion method. NBP-related components were widely distributed throughout the body, and high concentrations were detected in the stomach, small intestine, fat, bladder, kidney, liver and ovary. At 168 h after oral administration, the mean cumulative recovered radioactivity was 99.85% of the original dose, and was 85.12% in urine and 14.73% in feces. Metabolite profiles were detected via radiochromatography. A total of 49 metabolites were identified in rat plasma, urine, and feces. The main metabolic pathways were oxidation, glucuronidation, and sulfation. Overall, NBP was absorbed rapidly, distributed throughout the body, and excreted in the form of metabolites. Urine was the main excretion route, and the absorption, distribution, metabolism and excretion of NBP showed no significant gender difference between male and female rats.

A new learning and training technology for application of selfcontained breathing apparatus

People guard their respiratory organs during fire extinguishing and life-saving using self-contained breathing apparatuses (SCBA) and self-rescue devices. Learning and training of skills of using SCBA and self-rescuers have certain deficiencies. Despite detailed rules and requirements provided by the existing specification documents, SCBA training and mastering lack efficiency. Regarding the prevailing causes of this situation, first, the formalist approach to the specification compliance often consists in simple ticking on the plus side of the learning and training record and, second, there is a notorious &lsquo;human factor&rsquo;. In particular, in the course of massive learning and training, it is impossible to trace actions or psychological and physical response of an individual without attending each trainee with a personal and specially trained supervisor. The quality of training is however not guaranteed in this case. There is a high probability that a user unacquires the required skill and fails to use SCBA correctly in case of an actual accident. The peculiarities of learning and training are discussed, and the new technology and outfit are proposed. The technology and the recording simulator enable learning and training of people using SCBA in their work or in emergency response, ensures the maximum control and improves the unbiased appraisal of physical capabilities of personnel to enable correct selection and managerial decision-making. The information obtained using the proposed technology can make it possible to undertake anticipatory estimation and analysis of various performance scenarios, plans and routes of escape, evacuation and elimination of possible emergencies.

Urinary Steroid Profile in Elite Female Athletes in Relation to Serum Androgens and in Comparison With Untrained Controls.

IntroductionIn female athletes, the interpretation of doping tests is complex due to hormonal variations during the menstrual cycle and hormonal contraceptive use, both influencing the urinary steroid profile. Exercise is suggested to affect circulating steroid hormone levels, and in women, the urinary steroid profile differs between in competition testing and out of competition testing. No previous study has investigated the relationship between amount of exercise and the urinary steroid profile in female elite athletes.PurposeTo compare the urinary steroid profile between female Olympic athletes and age- and BMI-matched untrained controls, and to study the urinary steroid profile in relation to serum hormones and amount of exercise.MethodsIn this cross-sectional study conducted at the Women’s Health Research Unit, Karolinska University Hospital, Stockholm, 94 female elite athletes and 86 untrained controls were included. Serum estrogens and testosterone and the urinary steroid profile were analyzed by liquid chromatography–tandem mass spectrometry and gas chromatography-tandem mass spectrometry, respectively. Exercise hours/week were evaluated by questionnaire.ResultsAlthough serum steroid hormones were comparable between groups, the athletes demonstrated approximately 30% lower urinary steroid metabolites of testosterone, epitestosterone, androsterone, etiocholanolone, 5α-androstan-3α, 17β-diol, and 5β-androstan-3α, 17β-diol compared to the controls. The urinary steroid metabolites correlated positively with serum steroid hormones. In the athletes, urinary steroid metabolites: androsterone (rs = −0.28, p = 0.007), epitestosterone (rs = −0.22, p = 0.034), 5αAdiol (rs = −0.31, p = 0.002) and testosterone (rs = −0.24, p = 0.026), were negatively correlated with amount of training (hours per week).ConclusionThe urinary concentrations of steroid metabolites were lower in elite athletes than in sedentary controls, although serum steroids were comparable between groups. Moreover, exercise time was negatively associated with the urinary concentrations. Our findings suggest alternative excretion routes of androgens in the athletes related to training.

How Different Albumin-Binders Drive Probe Distribution of Fluorescent RGD Mimetics

The biodistribution of medical imaging probes depends on the chemical nature of the probe and the preferred metabolization and excretion routes. Especially targeted probes, which have to reach a certain (sub)cellular destination, have to be guided to the tissue of interest. Therefore, small molecular probes need to exhibit a well-balanced polarity and lipophilicity to maintain an advantageous bioavailability. Labelled antibodies circulate for several days due to their size. To alter the biodistribution behavior of probes, different strategies have been pursued, including utilizing serum albumin as an inherent transport mechanism for small molecules. We describe here the modification of an existing fluorescent RGD mimetic probe targeted to integrin αvβ3 with three different albumin binding moieties (ABMs): a diphenylcyclohexyl (DPCH) group, a p-iodophenyl butyric acid (IPBA) and a fatty acid (FA) group with the purpose to identify an optimal ABM for molecular imaging applications. All three modifications result in transient albumin binding and a preservation of the target binding capability. Spectrophotometric measurements applying variable amounts of bovine serum albumin (BSA) reveal considerable differences between the compounds concerning their absorption and emission characteristics and hence their BSA binding mode. In vivo the modified probes were investigated in a murine U87MG glioblastoma xenograft model over the course of 1 wk by fluorescence reflectance imaging (FRI) and fluorescence mediated tomography (FMT). While the unmodified probe was excreted rapidly, the albumin-binding probes were accumulating in tumor tissue for at least 5 days. Considerable differences between the three probes in biodistribution and excretion characteristics were proved, with the DPCH-modified probe showing the highest overall signal intensities, while the FA-modified probe exhibits a low but more specific fluorescent signal. In conclusion, the modification of small molecular RGD mimetics with ABMs can precisely fine-tune probe distribution and offers potential for future clinical applications.

Determinants for serum half-lives for linear and branched perfluoroalkyl substances after long-term, high exposure — a study in Ronneby, Sweden

BACKGROUND AND AIM: Per- and polyfluoroalkyl substances (PFAS) are persistent, ubiquitous substances with long elimination periods and various health effects. Although elimination rates and half-lives for PFAS have been described in both animal and human studies, few studies have explored the determinants behind the human elimination. The purpose of the current study was to estimate serum half-lives and the determinants for different PFAS. METHODS: Municipal drinking water contaminated with PFAS had been distributed to one third of households in Ronneby, Sweden. The source was firefighting foam used in a nearby airfield since the mid-1980s. Clean water was provided from December, 2013. Between 2014 and 2018, 114 individuals aged between 4-84 from Ronneby participated in up to 10 serum sampling occasions. Potential determinants were collected at baseline, including Age, Sex, Body Mass Index, and estimated Glomerular Filtration Rate (eGFR). Urine was collected three times for calculating urine/serum ratio of PFAS, and faeces once for faecal calprotectin and zonulin. 19 PFAS were analyzed, and 8 of them were increased in Ronneby: perfluorooctanoic acid (PFOA), perfluoropentane sulfonate (PFPeS), perfluorohexane sulfonate (PFHxS), perfluoroheptane sulfonate (PFHpS), linear perfluorooctane sulfonate (L-PFOS) and three branched perfluorooctane sulfonates (1m-PFOS, 3/4/5m-PFOS and 2/6m-PFOS). RESULTS:The mean estimated half-lives (in years) were 2.47 (95%CI 2.27-2.7) for PFOA, 0.94 (0.86-1.02) for PFPeS, 4.52 (4.14-4.99) for PFHxS, 4.55 (4.14-5.06) for PFHpS, 2.73 (2.55-2.92) for L-PFOS, 5.01 (4.56-5.55) for 1m-PFOS, 3.43 (3.19-3.71) for 3/4/5m-PFOS, and 2.67 (2.51-2.85) for 2/6m-PFOS. Young age (14), females in fertile age (14-50), high eGFR (90 ml/min/1.73 m²), high urine/serum ratio, high calprotectin and low zonulin were associated with shorter half-lives. CONCLUSIONS:These results provide observational support for elimination routes – renal, faecal and maternal; are in line with past estimates for some PFAS such as PFOA; and are the first results for different PFOS isomers. KEYWORDS: PFAS, Environmental Epidemiology, Water Quality, Long-term exposure

Clinical Pharmacokinetics and Pharmacodynamics of Cefiderocol.

Cefiderocol is a new broad-spectrum cephalosporin antibiotic with promising activity against various Gram-negative bacteria including carbapenem-resistant strains. A chlorocatechol group in the C-3 side chain provides cefiderocol with a siderophore activity, improving its stability against β-lactamases and facilitating the transportation of cefiderocol across outer bacterial membranes. Cefiderocol shows linear pharmacokinetics over a broad range of clinically relevant doses, with unchanged renal excretion constituting the main route of elimination. Geometric means (coefficient of variation) of the volume of distribution and clearance in individuals with normal kidney function were 15.8 (15%) L and 4.70 (27%) L/h, respectively. In patients with end-stage renal disease, clearance was 1.10 (24%) L/h. Time above the minimum inhibitory concentration is the main predictor of efficacy. There is no evidence for clinically relevant interactions of cefiderocol with other drugs mediated by metabolizing enzymes or drug transporters. Simulations based on population pharmacokinetic modeling suggest that dosing regimens should be adjusted based on kidney function to optimize therapeutic exposure to cefiderocol. Clinical efficacy trials indicated that cefiderocol is non-inferior to imipenem/cilastatin in the treatment of complicated urinary tract infections and acute uncomplicated pyelonephritis, and to meropenem in the treatment of nosocomial pneumonia. In the one study currently available, cefiderocol performed similarly to the best available therapy in the treatment of severe carbapenem-resistant Gram-negative infections regarding clinical and microbiological efficacy. In summary, cefiderocol shows favorable pharmacokinetic/pharmacodynamic properties and an acceptable safety profile, suggesting that cefiderocol might be a viable option to treat infections with bacteria resistant to other antibiotics.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40262-021-01063-5.

A population approach for the estimation of methylmercury ToxicoKinetics in red mullets

It is known that, as the vast majority of the anthropogenically emitted mercury can be found in aquatic ecosystems, where several methylating bacteria are present, fish consumption represents the most critical intake source of the most toxic form of mercury, the methylmercury (MeHg).The aim of this work is to predict MeHg levels in the fish muscles which, being the edible portion, are part of the human diet. A physiologically based toxicokinetics model was developed to evaluate the kinetics of MeHg in red mullets. Fishes were described by means of a multi-compartment model including stomach, gut, blood, muscles and an additional compartment virtually encompassing all the remaining organs. Absorption, distribution and excretion were modelled considering different MeHg routes of administration and excretion: intake by ingestion of contaminated food, intake and elimination through inhalation-exhalation and excretion through feces.The model has been firstly validated on Terapon jarbua fish (using the weighted least squares method for parameter estimation) to be subsequently readapted to predict methylmercury concentrations in the muscle of red mullets (using an approximate Bayesian computation approach).This simple multicompartmental model could be considered part, a link in the chain, of a wider more complex project aiming at tracking the fate of MeHg from polluted seawater to the human end consumer. The present study could be useful to surveillance organizations in order to carry out a more comprehensive and informed risk assessment analysis and to take appropriate preventive measures by evaluating possible new MeHg concentration thresholds to minimize public health hazards.

Evobrutinib, a covalent Bruton's tyrosine kinase inhibitor: Mass balance, elimination route, and metabolism in healthy participants.

The highly selective, covalent Bruton’s tyrosine kinase inhibitor evobrutinib is under investigation for treatment of patients with multiple sclerosis (MS). Early clinical studies in healthy participants and patients with relapsing MS indicated that evobrutinib is well‐tolerated and effective. We undertook a mass balance study in six men who received a single 75‐mg oral dose of evobrutinib containing ~ 3.6 MBq (100 μCi) 14C‐evobrutinib, to determine the absorption, metabolic pathways, and routes of excretion of evobrutinib. The primary objectives of this phase I study (NCT03725072) were to (1) determine the rates and routes of total radioactivity excretion, including the mass balance of total drug‐related radioactivity in urine and feces, (2) assess the pharmacokinetics (PKs) of total radioactivity in blood and plasma, and (3) characterize the plasma PKs of evobrutinib. Exploratory end points included identifying and quantifying evobrutinib and its metabolites in plasma and excreta (urine and feces) and exploring key biotransformation pathways and clearance mechanisms. Evobrutinib was primarily eliminated in feces (arithmetic mean percentage, SD, 71.0, 2.1) and, to a lesser extent, in urine (20.6, 2.0), with most of the total radioactivity (85.3%) excreted in the first 72 h after administration. No unchanged evobrutinib was detected in excreta. Evobrutinib was rapidly absorbed and substantially metabolized upon absorption. Only one major metabolite M463‐2 (MSC2430422) was identified in plasma above the 10% of total drug exposure threshold, which classifies M463‐2 (MSC2430422) as a major metabolite according to the US Food and Drug Administration (FDA; metabolites in safety testing [MIST]) and the European Medicines Agency (EMA; International Conference on Harmonization [ICH] M3). These results support further development of evobrutinib and may help inform subsequent investigations.

Osmium(II)-Coordination Induced C-C Bond Functionalization of Bis-lawsone.

Metal-coordination-driven C-C bond functionalization without involvement of the traditional route of oxidative addition, insertion, and reductive elimination has gained immense importance. In this context, the present Communication highlights the facile ring contraction process of the deprotonated bis-lawsone (L2-) to functionalized L12- upon coordination to {Os(bpy)2} or isomeric {Os(pap)2} (bpy = 2,2'-bipyridine and pap = 2-phenylazopyridine) in 1-3. Further, recognition of fractional redox noninnocence of L1 in 1+-3+ via experimental and theoretical events facilitated its inclusion in the redox noninnocent family.

Michael-Aldol Double Elimination Cascade to Make Pyridines: Use of Chromone for the Synthesis of Indolizines.

A domino Michael-aldol double elimination route to indolizines having two different acyl groups at the C5 and C7 positions is described where chromone is employed as a two-carbon unit for the synthesis of a pyridine moiety for the first time. Various analogues were readily accessed in good yields under metal-free and eco-friendly conditions. Further manipulation of the resulting products allowed entry to novel indolizine-heterocycle adducts, which are difficult to access by other methods.