Blood Area Under The Curve Research Articles

PSAT111 Neudesin Plasmatic Levels and Glucose Metabolism in Obese and Overweight Children: Preliminary Data

Abstract Neudesin, a newly discovered peptide mainly secreted in brain and adipose tissue, is under evaluation for its possible activity as negative regulator of energy expenditure. In pre-adipocyte cultures neudesin promotes adipogenesis, while in mice model neudesin decreases food intake. Childhood overweight and obesity are among the main health issues in modern times, especially in western countries, due to the association to increased cardiovascular and oncological risk in adult age. No data on neudesin in obese and overweight children are currently available. Given that, we aim to perform an observational cross-sectional study testing the hypothesis that neudesin plasmatic levels may be affected in obese and overweight children. We also evaluated any eventual relationship between neudesin and metabolic and anthropometric parameters to gain insight on a possible role in childhood obesity. 34 children were included in the study and divided in two groups according to Cole's criteria. Group A included obese and overweight children, 23 patients, 17 females (Tanner stage 1) and 6 males, aged 4-10 years; Group B included normal-weight children, 11 patients, 7 females (Tanner stage 1) and 4 males, aged 3-10 years. Metabolic (glucose and insulin, total - LDL - HDL-cholesterol, triglycerides, uric acid) and hormonal (fT3, fT4, TSH, IGF-1, leptin) parameters were evaluated. HOMA index, QUICKI index and the area under the curve (AUC) of glucose and insulin after oral glucose load were calculated in obese and overweight children. Neudesin was measured by ELISA system. Neudesin levels did not significantly differ between the two groups, even though a trend toward higher levels in group A was found (mean±SEM 3±0.32 ng/ml vs 1.98±0.15 ng/ml, p = 0.1). As expected, obese and overweight children showed significantly higher blood glucose, total and LDL cholesterol, triglycerides and leptin levels than those with normal weight. Interestingly, in obese and overweight children plasmatic neudesin levels significantly directly correlated with blood glucose and AUC of glucose. No other new significant correlation was detected in both groups. Very few data on serum neudesin levels in human are available. To note, neudesin was lower in obese adolescents compared to age-matched normal controls (1), while children affected by type 1 diabetes mellitus showed higher levels than age-matched controls (2). Taken together, these results, although preliminary, may suggest a possible age-related role of neudesin in glucose homeostasis in obese/overweight children.

Effect of the Intake of a Snack Containing Dietary Fiber on Postprandial Glucose Levels.

To examine the effects of the intake of a snack containing dietary fiber under free-living conditions on postprandial glucose levels in older adults, nine healthy older adults aged 76.9 ± 1.6 years (mean ± standard error) completed two crossover trials: 1) regular snack (BISCUIT) intake and 2) intake of snacks with a high dietary fiber content (DF-BISCUIT). In both trials, each participant consumed either BISCUIT or DF-BISCUIT between lunch and dinner time for 1 week. During the intervention, the blood glucose levels of all the subjects were observed using a continuous glucose monitoring system. Lower 24 h blood glucose levels were yielded in the DF-BISCUIT than the BISCUIT trials. Moreover, compared to the BISCUIT trials, the blood glucose levels after dinner and areas under the curve (AUCs) were significantly decreased in the DF-BISCUIT treatments. The blood glucose levels and AUCs after the intake of the next day’s breakfast were suppressed in the DF-BISCUIT treatments compared to those in the BISCUIT trials. Our data indicate that the intake of snacks with a high dietary fiber content under free-living conditions is an effective way to restrain postprandial glucose levels and that the effect lasts until breakfast the next day.

The Relationship Between Ingested Dose of Ethanol and Amount of Ethyl Glucuronide Formed in Blood.

A positive non-linear relation between the dose of ethanol ingested and the area under the curve (AUC) for ethyl glucuronide (EtG) in urine is previously observed. The relation between both doses and AUC of ethanol and the AUC for EtG in blood is not previously published, and this study aimed to investigate this relationship. After an overnight fast, 10 healthy volunteers ingested 0.5-g ethanol per kilo body weight (low dose) in one occasion and 1.0-g ethanol per kilo body weight (high dose) in the next occasion. Results showed that there was a significant higher median ratio between blood AUC for EtG and dose of ethanol in the high-dose (8.99; range 7.37–10.94) group compared to the low-dose (5.02; range 4.25–6.15) group (P = 0.005). The median ratio between the AUC for EtG and AUC for ethanol was actually significantly higher in the low-dose (1.77; range 1.51–2.24) group compared to the high-dose (1.67; range 1.30–2.02) group (P = 0.005), although values are quite similar. This study therefore showed that the ratio between the AUC for EtG in blood and dose of ethanol is higher after intake of 1.0 g/kg than 0.5 g/kg. This pattern is however not seen when AUC for EtG is compared to AUC for ethanol. Results therefore support that the percentage of ethanol converted to EtG is not increasing when the doses increase. An explanation for the positive non-linear relation previously observed between the dose of ethanol ingested and amount of EtG formed may be a relative higher first-pass metabolism of ethanol at lower doses.

Influence of PEG coating on the oral bioavailability of gold nanoparticles in rats

Metallic nanoparticles can be produced in a variety of shapes, sizes, and surface chemistries, making them promising potential tools for drug delivery. Most studies to date have evaluated uptake of metallic nanoparticles from the GI tract with methods that are at best semi-quantitative. This study used the classical method of comparing blood concentration area under the curve (AUC) following intravenous and oral doses to determine the oral bioavailability of 1, 2 and 5 kDa PEG-coated 5 nm gold nanoparticles (AuNPs). Male rats were given a single intravenous dose (0.8 mg/kg) or oral (gavage) dose (8 mg/kg) of a PEG-coated AuNP, and the concentration of gold was measured in blood over time and in tissues (liver, spleen and kidney) at sacrifice. Blood concentrations following oral administration were inversely related to PEG size, and the AUC in blood was significantly greater for the 1 kDa PEG-coated AuNPs than particles coated with 2 or 5 kDa PEG. However, bioavailabilities of all of the particles were very low (< 0.1%). Concentrations in liver, spleen and kidney were similar after the intravenous doses, but kidney showed the highest concentrations after an oral dose. In addition to providing information on the bioavailability of AuNPs coated with PEG in the 1–5 kDa range, this study demonstrates the utility of applying the blood AUC approach to assess the quantitative oral bioavailability of metallic nanoparticles.

Development of an inhalation unit risk factor for isoprene

A unit risk factor (URF) was developed for isoprene based on evaluation of three animal studies with adequate data to perform dose–response modeling (NTP, 1994, 1999; Placke et al., 1996). Ultimately, the URF of 6.2E-08 per ppb (2.2E-08 per μg/m3) was based on the 95% lower confidence limit on the effective concentration corresponding to 10% extra risk for liver carcinoma in male B6C3F1 mice after incorporating appropriate adjustment factors for species differences in target tissue metabolite concentrations and inhalation dosimetry. The corresponding lifetime air concentration at the 1 in 100,000 no significant excess risk level is 160 ppb (450 μg/m3). This concentration is almost 4400 times lower than the lowest exposure level associated with statistically increased liver carcinoma in B6C3F1 mice in the key study (700 ppm in Placke et al., 1996) and is above typical isoprene breath concentrations reported in the scientific literature. Continuous lifetime environmental exposure to the 1 in 100,000 excess risk level of 160 ppb would be expected to raise the human blood isoprene area under the curve (AUC) less than one-third of the standard deviation of the endogenous mean blood AUC. The mean for ambient air monitoring sites in Texas (2005–2014) is approximately 0.13 ppb.

SU‐E‐T‐45: Antibody Mean Residence Time in Blood and Its Correlation with Protein Molecular Weight

Purpose:Animal biodistribution data are required prior to introducing a new radiopharmaceutical into clinical trials. Protein engineering, using recombinant DNA techniques can produce a large number of related (cognate) antibodies to a given molecular target. Thus, it is important that these constructs be numerically related to one another via a single criterion. In the following, we use the mean residence time (MRT) in murine blood as this criterion.Methods:Five cognate anti‐CEA (Carcinoembryonic Antigen) antibodies were compared with regard to their MRT in whole blood of CEA‐positive tumor‐bearing (LS174T) mice. MRT was defined by blood AUC (area under the curve) divided by the initial blood uptake value; all in units of percent injected dose per gram (%ID/g). Cognates included single chain scFv (25 kDa), diabody (50 kDa), minibody (80 kDa), F(ab')2 (120 kDa), and intact (155 kDa) forms of the murine cT84.66 antibody against CEA. All were labeled with radioactive iodine.Results:The agents, in the sequence listed, exhibited MRT values of 1.16 +/‐ 0.01 h, 0.99 h, 5.06 +/‐ 0.70 h, 6.61 +/‐ 0.36 h, and 59.3 +/‐ 2.4 h respectively. Because of the monotonic nature of the sequence, a linear correlation analysis was performed between molecular weight (MW) and MRT or ln(MRT) of the 5 proteins. Probability of random correlation was 0.10 for MRT and 0.01 for ln(MRT).Conclusion:MRT values of cognate anti‐CEA antibodies were found to be a monotonically increasing sequence with respect to MW. Cognate MW values correlated best to ln(MRT) of the protein species. Thus MRT was proportional to an exponential function of molecular weight. The extended intact antibody circulation time presumably reflected its relatively maximal MW. Presence of an intact FC segment on this native antibody may also have influenced these results.

In Vivo Visualization and Quantification of (Disturbed) Oatp-Mediated Hepatic Uptake and Mrp2-Mediated Biliary Excretion of 99mTc-Mebrofenin in Mice

Hepatic transport of (99m)Tc-mebrofenin through organic anion transport protein 1a and 1b (Oatp1a/1b) and multidrug resistance protein 2 (Mrp2) was investigated by small-animal SPECT. On the basis of the results, a noninvasive method to visualize and quantify disturbances in hepatic transport is proposed. Friend virus B wild-type mice (untreated, bile duct-ligated, vehicle- or rifampicin-treated) and strain-matched knockout mice unable to express the uptake transporters Oatp1a/1b (Slco1a/1b(-/-)/(-/-)) or the efflux transporter Mrp2 (Abcc2(-/-)) were intravenously injected with (99m)Tc-mebrofenin (n = 3 per group). After dynamic small-animal SPECT and short CT acquisitions, time-activity curves of the liver and of the gallbladder and intestines were obtained and correlated with direct blood samples. Normal hepatobiliary clearance of (99m)Tc-mebrofenin was severely impaired in the bile duct-ligated animal, as evidenced by elevated hepatic tracer levels. In Slco1a/1b(-/-)/(-/-) mice, a lower area under the curve (AUC) for the liver (P = 0.014) was obtained and no activity was detected in the gallbladder and intestines. Renal rerouting was observed, along with an increase in the blood AUC (P = 0.01). Abcc2(-/-) mice had a higher liver AUC (P = 0.009), a delayed emergence time of (99m)Tc-mebrofenin in the gallbladder (P = 0.009), and a lower AUC for the gallbladder and intestines (P = 0.001). The blood curve was similar to that of wild-type mice. (99m)Tc-mebrofenin disposition was altered after rifampicin treatments. We observed a dose-dependent delayed time point at which tracer maximized in liver, an increased AUC for liver, and a lower AUC for gallbladder and intestines (P = 0.042, 0.034, and 0.001, respectively, highest dose). Emergence in the gallbladder occurred later (P = 0.009, highest dose), and blood AUC was higher (P = 0.006). The current study visualized and quantified hepatic uptake and biliary efflux of (99m)Tc-mebrofenin. Our results demonstrated the possibility of discriminating, on a quantitative level, between lack of functional activity of sinusoidal uptake versus that of biliary efflux transporters.

Measurement and Compartmental Modeling of the Effect of CYP3A5 Gene Variation on Systemic and Intrarenal Tacrolimus Disposition

We evaluated the hypothesis that cytochrome P450 3A5 (CYP3A5) expression can affect intrarenal tacrolimus accumulation. Tacrolimus was administered orally to 24 healthy volunteers who were selected on the basis of their CYP3A5 genotype. As compared with CYP3A5 nonexpressors, expressors had a 1.6-fold higher oral tacrolimus clearance and 2.0- to 2.7-fold higher metabolite/parent area under the curve (AUC) ratios for 31-desmethyl tacrolimus (31-DMT), 12-hydroxy tacrolimus, and 13-desmethyl tacrolimus (13-DMT). In addition, the apparent urinary tacrolimus clearance was 36% lower in CYP3A5 expressors as compared with nonexpressors. To explore the mechanism behind this observation, we developed a semiphysiological model of renal tacrolimus disposition and predicted that tacrolimus exposure in the renal epithelium of CYP3A5 expressors is 53% of that for CYP3A5 nonexpressors, when normalized to blood AUC. These data suggest that, at steady state, intrarenal accumulation of tacrolimus and its primary metabolites will depend on the CYP3A5 genotype of the liver and kidneys. This may contribute to interpatient differences in the risk of tacrolimus-induced nephrotoxicity.

Enhanced Systemic Tissue Distribution after Dermal versus Intravenous 3,3′,4,4′-Tetrachlorobiphenyl Exposure: Limited Utility of Radiolabel Blood Area under the Curve and Excretion Data in Dermal Absorption Calculations and Tissue Exposure Assessment

As a dioxin-like polychlorinated biphenyl (PCB), 3,3′,4,4′-tetrachlorobiphenyl (TCB) is receiving increasing research and regulatory interest due to its high toxicity and persistence in the environment. 14C-TCB was administered at an identical dose of 300 μg via the intravenous (iv) or dermal route to swine to examine the exposure route dependency of the relationship between tissue exposure and blood area under the curve (AUC) and the relationship between dermal absorption and excretion of radiolabel. After iv and dermal exposure, blood, urine, and feces samples were collected during the 11-day in vivo studies. At the end of the experiments, full mass balance studies were conducted to characterize tissue distribution of label. On average, over 70% of the applied dermal and iv doses were recovered. As expected, more than a 10-fold increase in blood AUC (0.49 vs 0.031, h · % dose/ml), plasma AUC (0.40 vs 0.038, h · % dose/ml), urine excretion (29 vs 2.3% of the applied dose), and fecal (30 vs 3.0% of the applied dose) excretion was determined after iv exposure compared to dermal exposure. However, we unexpectedly found that the tissue residue following iv exposure (8.0% of the applied dose) was only half that following dermal exposure (16% of the applied dose). Significantly larger (20- to 30-fold) ratios of blood AUC:tissue residue and excretion:tissue residue were observed after iv exposure compared to dermal exposure. This may indicate a route-related concentration–dependent blood-to-tissue partition process of pooled label, unique skin metabolism, or saturable hepatic metabolism of TCB. Thus, a long-term, low-input exposure pattern similar to this dermal exposure could be more harmful to systemic tissues than a short-term, high-dose exposure similar to this iv exposure. One should be aware that greater absorption, higher blood concentrations, greater blood and plasma AUCs, and greater excretion of label do not necessarily result in a greater overall tissue exposure and that some conventional approaches using label determination in blood and excreta without full mass balance studies may underestimate dermal absorption of chemicals similar to TCB.

Serial blood lactate levels can predict the development of multiple organ failure following septic shock

Despite successful initial resuscitation, septic shock frequently evolves into multiple system organ failure (MSOF) and death. Since blood lactate levels can reflect the degree of cellular derangements, we examined the relation between serial blood lactate levels and the development of MSOF, or mortality, in patients with septic shock. In 87 patients with a first episode of septic shock, we measured initial lactate (at onset of septic shock), final lactate (before recovery or death), "lactime" (time during which blood lactate was > 2.0 mmol/L, and the area under the curve (AUC) for abnormal values (above 2.0 mmol/L). These measurements were correlated with survival and organ failure and scored for four systems (ie, respiratory, renal, hepatic, and coagulation), adding to a maximal score of 8. Thirty-three (38%) patients survived. Of the 54 (62%) nonsurvivors, the 13 patients who died during the first 24 hours of septic shock had higher initial blood lactate levels than those who died later (mean +/- standard deviation 9.6 +/- 5.3 mmol/L versus 5.6 +/- 3.7 mmol/L, P< 0.05). The 74 patients who survived the first 24 hours of shock, were studied in more detail. On presentation, survivors had a significantly higher mean arterial pressure (76 +/- 12 mm Hg versus 63 +/- 20 mm Hg, P < 0.001) and arterial pH (7.40 +/- 0.07 versus 7.37 +/- 0.09, P< 0.05) than nonsurvivors. Although the differences in initial blood lactate levels between survivors and nonsurvivors did not reach statistical significance (4.7 +/- 2.5 mmol/L versus 5.6 +/- 3.7 mmol/L), only the survivors had a significant decrease during the first 24 hours of septic shock. The survivors had a significantly lower lactime and AUC than the nonsurvivors. The duration of lactic acidosis was the best predictor of survival (multiple regression analysis, R2 = 0.266, P <0.001), followed by age, heart rate, and mean arterial pressure. Patients with lower organ failure scores had lower initial blood lactate, lactime, and AUC. The duration of lactic acidosis was the only significant predictor of organ failure. In patients with septic shock, serial determinations of blood lactate levels are good predictors of the development of MSOF an death. In this respect, the duration of lactic acidosis is more important than the initial lactate value. Although a number of factors may contribute to hyperlactatemia, these observations are compatible with a direct role of prolonged tissue hypoxia in the development of complications following septic shock.

Human Variability in Susceptibility to Toxic Chemicals— A Preliminary Analysis of Pharmacokinetic Data from Normal Volunteers

The tenfold "uncertainty" factor traditionally used to guard against human interindividual differences in susceptibility to toxicity is not based on human observations. To begin to build a basis for quantifying an important component of overall variability in susceptibility to toxicity, a data base has been constructed of individual measurements of key pharmacokinetic parameters for specific substances (mostly drugs) in groups of at least five healthy adults. 72 of the 101 data sets studied were positively skewed, indicating that the distributions are generally closer to expectations for log-normal distributions than for normal distributions. Measurements of interindividual variability in elimination half-lives, maximal blood concentrations, and AUC (area under the curve of blood concentration by time) have median values of log10 geometric standard deviations in the range of 0.11-0.145. For the median chemical, therefore, a tenfold difference in these pharmacokinetic parameters would correspond to 7-9 standard deviations in populations of normal healthy adults. For one relatively lipophilic chemical, however, interindividual variability in maximal blood concentration and AUC was 0.4--implying that a tenfold difference would correspond to only about 2.5 standard deviations for those parameters in the human population. The parameters studied to date are only components of overall susceptibility to toxic agents, and do not include contributions from variability in exposure- and response-determining parameters. The current study also implicitly excludes most human interindividual variability from age and illness. When these other sources of variability are included in an overall analysis of variability in susceptibility, it is likely that a tenfold difference will correspond to fewer standard deviations in the overall population, and correspondingly greater numbers of people at risk of toxicity.