Body Tissue Distribution Research Articles

Pharmacokinetics, absorption, distribution, metabolism and excretion of the MEK inhibitor zapnometinib in rats.

Zapnometinib is a MEK inhibitor currently under clinical development for the treatment of COVID-19 and influenza. Zapnometinib has both antiviral and immunomodulatory effects. Information concerning the absorption, distribution, metabolism, and excretion of the compound following single oral doses of 30mg/kg [14C]-zapnometinib to rats was required to support pharmacology and toxicology studies in animals and clinical studies in man. As part of the development and safety assessment of this substance, zapnometinib was radioactively labeled and used for the investigation of time-dependent plasma concentrations, the rates and routes of excretion, the extent and time-course of compound distribution in body tissues, the metabolite profiles in plasma, urine and feces and the chemical nature of its metabolites. The present study reveals a rapid but low absorption of zapnometinib from the gastrointestinal tract, with more than 90% of the compound being excreted within 48h, mainly via feces. Whole body autoradiography confirms that zapnometinib was rapidly and widely distributed, with greatest concentrations in the circulatory and visceral tissues. Maximum plasma and tissue concentrations occurred between two and 8h post dose. Penetration into the brain was low, and elimination from most tissues almost complete after 168h. Metabolic profiles showed that the main clearance routes were metabolism via oxidative reactions and glucuronidation. These results further strengthen the knowledge of zapnometinib with respect to the clinical development of the drug.

Body composition and composition of gain of growing beef bulls fed rations with varying energy concentrations

Data on chemical body composition of cattle serve as a basis for recommendations on energy and nutrient requirements. Relevant data of growing dual-purpose Fleckvieh (German Simmental) bulls are scarce and originate from old trials, covering low rates of gain and live weights. Hence, the aim of the study was to analyze the body tissue distribution, chemical composition, and composition of body weight gain of growing Fleckvieh bulls within a 120–780 kg live weight range. Results showed that body composition changed during growth but was not affected by dietary energy concentration. Changes in body composition were characterized by increasing shares of fat tissue and ether extract. Body tissues as blood, organs, gastrointestinal tract, and bone proportionately decreased during growth, while muscle and tendon proportions remained constant. The bulls featured enhanced growth potential and high muscle and protein gain throughout the described weight range. The requirements for metabolizable protein in relation to energy decrease with increasing live weight of the animals.

"Bioelectrical impedance analysis in managing sarcopenic obesity in NAFLD".

IntroductionSarcopenic obesity and its association with nonalcoholic fatty liver disease (NAFLD) is under‐recognized by many healthcare providers in Western medicine due to the lack of awareness and diagnostic guidelines. The result is delayed recognition and treatment, which leads to further health deterioration and increased healthcare costs. Sarcopenic obesity is characterized by the presence of increased fat mass in combination with muscle catabolism related to chronic inflammation and/or inactivity. Previous research has recommended evaluating body composition and physical function performance to adequately diagnose sarcopenic obesity. Body composition analysis can be performed by imaging applications through magnetic resonance imaging, computed tomography, and dual‐energy x‐ray absorptiometry. Due to the cost of each device and radiation exposure for patients as evidenced in all three modalities, bioelectrical impedance analysis offers a noninvasive approach capable of providing quick and reliable estimates of lean body and fat mass.Methods and ResultsThis review analyzes the current evidence‐based literature, indicating a lower skeletal muscle mass and increased visceral adipose tissue correlation to the advancement of fibrosis in fatty liver disease.ConclusionGiven the substantial promising research conducted in predominantly Asian populations regarding body tissue distribution and NAFLD, additional prospective research is needed to extend these findings in Western populations.

Mercury in raw and cooked shrimp and mussels and dietary Brazilian exposure

Seafood is the main source of dietary mercury (Hg) exposure and it can be affected by species, origin, tissue, and processing. The objective of this study was to investigate total Hg in shrimp and mussels from the retail market, compare species, body tissue distribution and cooking time, and to estimate dietary exposure. A total of 126 samples (whiteleg and Atlantic seabob shrimp and South American mussel) were analyzed. Total mercury was quantified by combustion atomic absorption spectrometry with gold amalgamation. Every sample had total Hg lower than maximum legislation levels. Higher mean levels were found in mussels compared to shrimp; and whiteleg shrimp had higher mean Hg levels compared to Atlantic seabob (p < 0.05). Mercury levels in the muscle were higher than in the exoskeleton. Boiling for up to 4 and 6 min did not affect Hg levels in shrimp and mussels, respectively. The estimated methylmercury (MeHg) mean intake from the consumption of shrimp and mussels (0.04–0.09 μg/kg bw for 3 portions/week consumption) was low, less than 6% of the provisional tolerable weekly intake – PTWI.

18F-Labeled perfluorocarbon droplets for positron emission tomography imaging

IntroductionNanoscale perfluorocarbon (PFC) droplets have been used to create imaging agents and drug delivery vehicles. However, development and characterization of new formulations of PFC droplets are hindered because of the lack of simple methods for quantitative and sensitive assessment of whole body tissue distribution and pharmacokinetics of the droplets. To address this issue, a general-purpose method for radiolabeling the inner core of nanoscale perfluorocarbon droplets with a hydrophobic and lipophobic fluorine-18 compound was developed, so that positron emission tomography (PET) and quantitative biodistribution studies can be employed to evaluate PFC nanodroplets in vivo. MethodsA robust method to produce [18F]CF3(CF2)7(CH2)3F from a tosylate precursor using [18F]F− was developed. The product's effectiveness as a general label for different PFCs and its ability to distinguish the in vivo behavior of different PFC droplet formulations was evaluated using two types of PFC nanodroplets: fluorosurfactant-stabilized perfluorohexane (PFH) nanodroplets and lipid-stabilized perfluorooctylbromide (PFOB) nanodroplets. In vivo assessment of the 18F-labeled PFH and PFOB nanodroplets were conducted in normal mice following intravenous injection using small animal PET imaging and gamma counting of tissues and fluids. Results[18F]CF3(CF2)7(CH2)3F was produced in modest yield and was stable with respect to loss of fluoride in vitro. The labeled fluorocarbon was successfully integrated into PFH nanodroplets (~175 nm) and PFOB nanodroplets (~260 nm) without altering their mean sizes, size distributions, or surface charges compared to their non-radioactive analogues. No leakage of the radiolabel from the nanodroplets was detected after droplet formation in vitro. PET imaging and biodistribution data for the two droplet types tested showed significantly different tissue uptake and clearance patterns. ConclusionA convenient method for producing 18F-labeled PFC droplets was developed. The results highlight the potential utility of the strategy for pre-clinical evaluation of different PFC droplet formulations through direct PFC core labeling using a fluorinated radiolabel.

Sedentary behavior and compensatory mechanisms in response to different doses of exercise-a randomized controlled trial in overweight and obese adults.

To examine compensatory changes in sedentary behavior (SB) and light-intensity physical activities (LIPA) in response to a 22-week exercise training program in overweight/obese adults; and to determine if different forms of exercise training and physical activity recommendations interact with these compensatory changes. Eighty-nine overweight and obese individuals (body mass index (BMI): 25-34.9 kg/m2, 48% males), aged 18-50 years, were randomized into four intervention groups (strength, endurance, combined strength + endurance and physical activity recommendations) with a 25-30% caloric restriction of total daily energy expenditure for 22 weeks. Energy expenditure was measured by accelerometry before, during and after the program. LIPA increased significantly (P<0.001) after three months and at the end of intervention compared to baseline (pre: 281±9 min; 3 months: 303±9 min; post: 312±8 min). SB percentage decreased by 5.3 at the end of the intervention (P=0.002). No interactions were observed between groups or sexes. Significant correlations were found between SB and body weight, fat mass, android fat mass and lean body mass before and after the intervention (P<0.05). LIPA was also significantly correlated with all these body composition variables in the pre-intervention, but only correlated with body weight at the end of intervention. There were no compensatory changes after a combined exercise and diet program; where minutes in LIPA increased and %SB decreased after the program, without differences among exercise modes. Greater physical activity levels can contribute to a better percentage and distribution of body tissues.

Body composition in adults with neurofibromatosis type 1.

To evaluate the body composition and nutritional status of neurofibromatosis type 1 (NF1) adult patients. A cross-sectional study of 60 NF1 patients (29 men, 31 women) aged ≥ 18 years who were evaluated from September 2012 to September 2013 in a Neurofibromatosis Outpatient Reference Center. Patients underwent nutritional assessment including measurements of weight, stature, waist circumference (WC), upper-arm circumference (UAC), and skinfolds (biceps, triceps, subscapular, suprailiac). Body mass index (BMI), upper-arm total area (UATA), upper-arm muscle area (UAMA), upper-arm fat area (UAFA), body fat percentage (BFP), fat mass, fat-free mass, fat mass index, and fat-free mass index were also calculated. The mean age of the study population was 34.48±10.33 years. The prevalence of short stature was 28.3%. Low weight was present in 10% of the sample and 31.7% of patients had a BMI ≥ 25 kg/m2. Reduced UAMA (<5th percentile) was present in 43.3% and no difference was found in UAFA between the sexes. The BFP was considered high in 30% and 17 (28.3%) patients had a WC above the World Health Organization cutoffs. In this study, NF1 patients had a high prevalence of underweight, short stature, and reduced UAMA, with no difference between the sexes. Reduced UAMA was more prevalent in underweight patients; however, this was also observed in the normal and overweight patients. Further studies should investigate the distribution of body tissues in NF1 patients, including differences between men and women, and the influence of diet and nutrition on clinical features in NF1.

Use of Anthropometry for the Prediction of Regional Body Tissue Distribution in Adults: Benefits and Limitations in Clinical Practice

Use of Anthropometry for the Prediction of Regional Body Tissue Distribution in Adults: Benefits and Limitations in Clinical Practice

Use of Anthropometry for the Prediction of Regional Body Tissue Distribution in Adults: Benefits and Limitations in Clinical Practice

Use of Anthropometry for the Prediction of Regional Body Tissue Distribution in Adults: Benefits and Limitations in Clinical Practice

Use of anthropometry for the prediction of regional body tissue distribution in adults: benefits and limitations in clinical practice.

Regional body composition changes with aging. Some of the changes in composition are considered major risk factors for developing obesity related chronic diseases which in turn may lead to increased mortality in adults. The role of anthropometry is well recognized in the screening, diagnosis and follow-up of adults for risk classification, regardless of age. Regional body composition is influenced by a number of intrinsic and extrinsic factors. Therapeutic measures recommended to lower cardiovascular disease risk include lifestyle changes. The aim of this review is to systematically summarize studies that assessed the relationships between anthropometry and regional body composition. The potential benefits and limitations of anthropometry for use in clinical practice are presented and suggestions for future research given.

Thomas Alfred Plumley

The aim of this study was to determine the plasma levels and the tissue distribution of otilonium bromide, measured as total radioactivity, after oral administration of 2 mg/kg of¹⁴C-labeled drug...

A commonly used rumen-protected conjugated linoleic acid supplement marginally affects fatty acid distribution of body tissues and gene expression of mammary gland in heifers during early lactation

BackgroundConjugated linoleic acids (CLA) in general, and in particular the trans-10,cis-12 (t10,c12-CLA) isomer are potent modulators of milk fat synthesis in dairy cows. Studies in rodents, such as mice, have revealed that t10,c12-CLA is responsible for hepatic lipodystrophy and decreased adipose tissue with subsequent changes in the fatty acid distribution. The present study aimed to investigate the fatty acid distribution of lipids in several body tissues compared to their distribution in milk fat in early lactating cows in response to CLA treatment. Effects in mammary gland are further analyzed at gene expression level.MethodsTwenty-five Holstein heifers were fed a diet supplemented with (CLA groups) or without (CON groups) a rumen-protected CLA supplement that provided 6 g/d of c9,t11- and t10,c12-CLA. Five groups of randomly assigned cows were analyzed according to experimental design based on feeding and time of slaughter. Cows in the first group received no CLA supplement and were slaughtered one day postpartum (CON0). Milk samples were taken from the remaining cows in CON and CLA groups until slaughter at 42 (period 1) and 105 (period 2) days in milk (DIM). Immediately after slaughter, tissue samples from liver, retroperitoneal fat, mammary gland and M. longissimus (13th rib) were obtained and analyzed for fatty acid distribution. Relevant genes involved in lipid metabolism of the mammary gland were analyzed using a custom-made microarray platform.ResultsBoth supplemented CLA isomers increased significantly in milk fat. Furthermore, preformed fatty acids increased at the expense of de novo-synthesized fatty acids. Total and single trans-octadecenoic acids (e.g., t10-18:1 and t11-18:1) also significantly increased. Fatty acid distribution of the mammary gland showed similar changes to those in milk fat, due mainly to residual milk but without affecting gene expression. Liver fatty acids were not altered except for trans-octadecenoic acids, which were increased. Adipose tissue and M. longissimus were only marginally affected by CLA supplementation.ConclusionsDaily supplementation with CLA led to typical alterations usually observed in milk fat depression (reduction of de novo-synthesized fatty acids) but only marginally affected tissue lipids. Gene expression of the mammary gland was not influenced by CLA supplementation.

Efficiency correction factors of an ACCUSCAN whole-body counter due to the biodistribution of 134Cs, 137Cs and 60Co

The efficiency calibration of whole-body counters (WBCs) for monitoring of internal contaminations is usually performed with anthropomorphic physical phantoms assuming homogeneous activity distribution. Besides the inherent limitations of these phantoms in resembling the human anatomy, they do not represent a realistic activity distribution, since in real situations each incorporated radionuclide has its particular biodistribution after entering the systemic circulation. Moreover, the activity content in the different organs and tissues comprising the biokinetics is time dependent. This work aims at assessing the whole-body counting efficiency deviations arising from considering a detailed voxel phantom instead of a standard physical phantom (BOMAB) and at evaluating the effect of the anatomical differences between both phantoms. It also aims at studying the efficiency considering the biodistribution of a set of radionuclides of interest incorporated in the scope of environmental and occupational exposures (inhalation and ingestion) and at computing the time-dependent efficiency correction factors to account for the biodistribution variation over time. For the purpose, Monte Carlo (MC) simulations were performed to simulate the whole-body counting efficiencies and biokinetic models were used to estimate the radionuclides' biokinetic behaviour in the human body after intake. The comparison between the efficiencies obtained with BOMAB and the voxel phantom showed deviations between 1.8 and 11.7 %, proving the adequacy of the BOMAB for WBC calibration. The obtained correction factors show that the effect of the biodistribution in the whole-body counting efficiency is more pronounced in cases of acute activity uptake and long-term retention in certain organs than in cases of homogeneous distribution in body tissues, for which the biokinetics influence can be neglected. This work further proves the powerful combination of MC simulation methods using voxel phantoms and biokinetic models for internal dosimetry studies.

Direct relationship of body mass index and waist circumference with body tissue distribution in elderly persons.

To explore the relationship of BMI and WC with muscle/adipose tissue mass ratios and with trunk adipose tissue distribution, based on an anatomical 5-compartment model, by dissection of cadavers of elderly persons. Cross-sectional explorative study. Brussels Cadaver Analysis Study. Cadavers of twenty-nine white Caucasian elderly persons (17 females and 12 males, aged 78.1±6.9 years). Whole body and trunk composition were determined at the anatomical tissue-system level by direct dissection. BMI and WC were significantly and positively related to absolute tissue masses in both sexes. Muscle tissue mass, adipose tissue mass and trunk internal adipose tissue mass correlated better with BMI (r-values between 0.68 and 0.89) than with WC (r-values between 0.49 and 0.71). BMI was significantly and inversely related with various muscle/adipose tissue ratios in both sexes (r-values between -0.54 and -0.68). WC correlated with muscle/adipose tissue ratios in females only (r-values between -0.55 and -0.64). BMI was also significantly related to trunk adipose tissue distribution in elderly females, but not in males. When comparing individual tissue proportions within and between adjacent BMI-classifications or WC categories, body composition varied considerably. Our results show that BMI and WC are significantly related with adipose tissue mass and with several ratios of muscle to adipose tissue in elderly subjects. However, cautious clinical interpretation is warranted since important differences in tissue mass proportions were found in subjects with similar BMI and/or WC values.

Clinicopathological Characterization in Poultry of Three Strains of Newcastle Disease Virus Isolated From Recent Outbreaks

Newcastle disease is a severe threat to the poultry industry and is caused by Newcastle disease virus, a member of the genus Avulavirus, family Paramyxoviridae. The virus is rapidly evolving, and several new genotypes have been discovered in the past few years. Characterization of these strains is important to evaluate field changes, anticipate new outbreaks, and develop adequate control measures. Three Newcastle disease isolates (APMV-1/duck/Vietnam, Long Bien/78/2002, APMV-1/chicken/Australia/9809-19-1107/1998, and APMV-1/double-crested cormorant/USA, Nevada/19529-04/2005) from recent outbreaks were investigated via clinicopathological assessment, immunohistochemistry (IHC), in situ hybridization, virus isolation, and serology in experimentally infected 4-week-old chickens. Phylogenetic studies showed that Australia isolate belongs to class II genotype I, Long Bien to class II genotype VIId, and Nevada cormorant to class II genotype V. Even though all 3 viruses had a virulent fusion protein cleavage site and ICPI values greater than 1.5, they all differed in their ability to cause clinical signs, in their lesions, and in their viral distribution in body tissues. The Long Bien isolate showed the most severe clinicopathological picture and the most widespread viral distribution. The Australia and Nevada cormorant isolates had a milder pathological phenotype, with viral replication restricted to only a few organs. The variability in clinicopathological characteristics despite the similarity in ICPI suggests that full clinicopathological assessment is necessary to fully characterize new isolates and that there are differences in pathogenesis among viruses of different genotypes.

Molecular Cloning and Functional Expression of Atlantic Salmon Peptide Transporter 1 in Xenopus Oocytes Reveals Efficient Intestinal Uptake of Lysine-Containing and Other Bioactive Di- and Tripeptides in Teleost Fish1–4

Atlantic salmon (Salmo salar L.) is one of the most economically important cultured fish and also a key model species in fish nutrition. During digestion, dietary proteins are enzymatically cleaved and a fraction of degradation products in the form of di- and tripeptides translocates from the intestinal lumen into the enterocyte via the Peptide Transporter 1 (PepT1). With this in mind, a full-length cDNA encoding the Atlantic salmon PepT1 (asPepT1) was cloned and functionally characterized. When overexpressed in Xenopus laevis oocytes, asPepT1 operated as a low-affinity/high-capacity transport system, and its maximal transport activity slightly increased as external proton concentration decreased (varying extracellular pH from 6.5 to 8.5). A total of 19 tested di- and tripeptides, some with acknowledged bioactive properties, some containing lysine, which is conditionally growth limiting in fish, were identified as well transported substrates, with affinities ranging between ∼0.5 and ∼1.5 mmol/L. Analysis of body tissue distribution showed the highest levels of asPepT1 mRNA in the digestive tract. In particular, asPepT1 mRNA was present in all segments after the stomach, with higher levels in the pyloric caeca and midgut region and lower levels in the hindgut. Depriving salmon of food for 6 d resulted in a ∼70% reduction of intestinal PepT1 mRNA levels. asPepT1 will allow systematic in vitro analysis of transport of selected di- and tripeptides that may be generated in Atlantic salmon intestine during gastrointestinal transit. Also, asPepT1 will be useful as a marker to estimate protein absorption function along the intestine under various physiological and pathological conditions.

Mammalian carotenoid absorption and metabolism

Abstract

Pathologic changes, tissue distribution, and extent of conversion to ethylenethiourea after subacute administration of zinc ethylene-bis-dithiocarbamate (zineb) to calves with immature rumen function

SUMMARY The toxicity of zinc ethylene-bis-dithiocarbamate (zineb), a widely used fungicide, was studied in four 4-week-old Friesian calves with immature rumen function. Calves were first subjected to liver biopsy, and thereafter, 3 of them were orally administered 200 mg of zineb/kg of body weight daily for 80 days, whereas the fourth calf served as control and remained untreated. Clinical, hematologic, and pathologic (including ultrastructural) findings were recorded. The distribution in body fluids and tissues of the parent compound and one of its main metabolites, ethylenethiourea (etu), also was examined. Treated calves had unthrifty appearance and reduction in weight gain. They also had remarkable impairment of thyroid function, as reflected by reduction in serum concentrations of triiodothyronine and thyroxine and increase in weight of the thyroid gland associated with epithelial vacuolization and foci of hyperplasia. Moderate increase in liver glycogen content and impairment in maturation of germ cells were recorded consistently. Whereas zineb was widely distributed in body tissues, etu accumulated mainly in the liver and the thyroid gland, although noticeable concentrations also were attained in muscle. Data were consistent with involvement of etu mainly in the pathogenesis of thyroid gland lesions, and indicate that unweaned calves given zineb develop a clinicopathologic syndrome that does not differ qualitatively from that already described in adult cattle exposed to zineb.

Toxicity and tissue distribution of pentachlorophenol and permethrin in pipistrelle bats experimentally exposed to treated timber

The dependence of bats in Britain on houses as roosts may result in them being exposed to pesticides used in remedial timber treatments. Pentachlorophenol (PCP) and permethrin are used as a fungicide and an insecticide for timber treatment, respectively. The present study investigated toxicity and distribution in body tissues of these two pesticides in pipistrelle bats. Four groups of nine to ten bats were kept in separate outdoor flight enclosures and were provided with roost boxes treated with either PCP only, permethrin, PCP/permethrin mixture or solvent only (control). At the start of the experiment, mean (±SE) PCP and permethrin concentrations on the surface of wooden blocks that had been treated in the same way as roost boxes were 69·32±6·76 mg g −1 ( n = 6) and 3·3±1·6 mg g −1 ( n = 3), respectively. All bats exposed to PCP and PCP/permethrin treated boxes died within 24 and 120 h, respectively; nine out of the ten controls survived the 32 day experimental period ( P < 0·001; both groups compared with control). Bats exposed to permethrin treated boxes survived as well as controls. Mean (±SE) carcass PCP concentration (excluding deposits on fur) of bats exposed to PCP and PCP/permethrin treated boxes was 13·11±2·52 μg g −1 BW ( n = 20). PCP burdens on fur were positively correlated with total weight of PCP in the carcass ( P < 0·001). PCP was present in fat depots, liver, kidney and the remainder of the body which, despite containing low PCP concentrations, was the main PCP reservoir (66·4±5·0% of carcass PCP load; n = 20). Total PCP in the carcass was significantly correlated with lipid weight ( P < 0·005). Permethrin was not detectable in body washes and tissues of bats exposed to PCP/permethrin mixture or permethrin.

γ-Endorphin-Generating Endopeptidase: Distribution in Body Tissues and Cellular Localization in Rat Testis*

The Leu17-Phe18 bond of beta-endorphin is cleaved by a specific endopeptidase that generates the biologically active peptide gamma-endorphin. gamma-Endorphin-generating endopeptidase (gamma EGE) activity was determined by a radiometric assay, using as substrate a radioactively labeled, N- and C-terminally protected pentapeptide: Ac-Val-Thr-Leu-Lys( [14C]CH3)2-NHCH3, a derivative of beta-endorphin-(15-19). Here we report the tissue distribution of gamma EGE activity and its cellular localization in the testis. gamma EGE activity was present in the cytosolic fraction of most tissues. Highest specific activity occurred in the testis, ovary, and the uterus (10-16 nmol X mg protein-1 X h-1). In testis highest specific gamma EGE activity was found in the tubules (42 nmol X mg protein-1 X h-1) and lowest in Leydig cells (8 nmol X mg protein-1 X h-1). Further fractionation of the tubules showed that the germinal cell fraction had a higher specific activity (24 nmol X mg protein-1 X h-1) than the Sertoli cell fraction (8 nmol X mg protein-1 X h-1). In testis depleted of the germinal cells by prenatal irradiation of the rat or hypophysectomy, specific activity of gamma EGE activity decreased 50-fold and 4-fold, respectively. In testis depleted of Leydig cells by treatment of rats with ethane dimethyl sulfonate, specific gamma EGE activity did not decrease. Adrenalectomy had no effect on the enzyme activity. The results suggest that the germinal cells are sites of processing of beta-endorphin into alpha- and gamma-endorphins. It is concluded that 1) gamma EGE activity is widely distributed in tissues; 2) highest gamma EGE activity is located in reproductive tissues; and 3) in the testis gamma EGE activity is mainly associated in the germinal cells.