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Plasma Concentrations 3.1.



  • Plasma Concentrations 3.1.
  • Pharmacokinetics
  • 1 Introduction
  • Stomach or plasma levels of n-decanoyl ghrelin, another acyl from of ghrelin, can be Plasma levels of intact and degraded ghrelin in patients with AN. Nevirapine plasma concentrations and concomitant use of rifampin in In the rifampin group seven nevirapine trough concentrations were low ( mg/l). Endogenous hydrocortisone plasma concentrations and their relationship to in plasma for ± days (LLOQ: μg/L) and in urine for ± days.

    Plasma Concentrations 3.1.

    Rats were fasted overnight before the surgery. After a midline incision of 3—4 cm to gain abdominal access, the total length of the small intestine was measured. The earlier defined jejunum was anastomosed by end-to-side duodenoenterostomy in order to restore continuity, excluding the duodenum and parts of the small intestine bowel. After blood sampling the tissues were harvested and the animals were euthanized. Four microliters of diluted 1: Normalisation was performed to a reference index obtained by calculating the geometric mean of reference gene Pum1 , Rpl37a , and Tbp expression.

    The fold change of analyzed gene expression level was calculated as a difference between normalised values obtained from the same animal before and after surgery.

    Statistical significance was set at a p value below 0. All tests were two-tailed. Distribution of variables was evaluated by the Shapiro-Wilk test and the quantile-quantile plot- homogeneity of variances was assessed by the Levene test.

    In case of skewed data distribution, logarithmic transformation was done before analysis. Briefly, DJOS surgery was shown to have very little impact on body weight reduction. In the DJOS groups, the body weight had no negative effect on insulin levels, glucose tolerance, or liver fat deposition. Changes in diet after surgery influenced the glucose stimulated insulin secretion.

    For most of the analyzed hepatokines, their plasma concentrations were higher after DJOS surgery when a comparison between surgery and type of diet used was conducted. Table 1 also shows differences in gene expression of Rbp4 , Ahsg , and Fgf21 in the liver tissues of animals after both types of surgery.

    Significant differences in gene expressions were deduced from two-way ANOVA analysis between type of surgery, groups, and interaction between group and operation type. When the two-way analysis of variance showed that one of the main analyzed factors is statistically significant and when also, but not necessarily, interaction between two main factors occurs, then contrast analysis can be performed.

    It means that we can compare each subclass of the first factor between groups defined by the first factor p value for comparisons between types of operation, SHAM and DJOS and each subclass of the second factor between groups defined by the first factor p value for comparisons between diets, i.

    Multiple comparisons in contrast analysis of hepatokines plasma levels in DJOS and SHAM operated groups in relation to diet used before and after surgery are presented in Table 2. Type of surgery, diet, and interaction between group and operation type had significant impact on the Rbp4 liver expression Table 1.

    The Ahsg expression in DJOS operated animals was higher in the group kept on a HF diet before and after the surgery as compared with other groups Figure 3 b , Tables 1 and 2.

    Diet and interaction between group and operation type had significant impact on the Fgf21 liver expression Table 1. To better understand the metabolic changes under the conditions of obesity, we have here analyzed selected hepatokines in relation to different dietary patterns in combination with duodenal exclusion. We can state the following: DJOS surgery was shown to significantly decrease the RBP4 plasma levels and Rbp4 expression level in the liver of rats, regardless of diet used before or after surgery as compared with SHAM operated animals.

    Nevertheless, regardless of the type of surgery, HF or mixed type of dietary pattern stimulated Rbp4 expression and increased plasma concentration of RBP4 when compared to the control diet. RBP4 is synthesized by hepatocytes and—to a lesser extent—by adipocytes. It is responsible for retinol transport from the liver to peripheral tissues [ 21 ]. Overexpression of Rbp4 in adipocytes is reported in the conditions of insulin resistance, metabolic syndrome, and obesity [ 7 ].

    Our results are consistent with other observations obtained on animals models, which show that injection of RBP4 into mice or transgenic overexpression of Rbp4 in mice leads to impaired insulin signalling in the skeletal muscle tissue and influences the activity of the gluconeogenic enzymes in the liver [ 22 ].

    Based on our results, we can suggest a strong relationship between the plasma concentration of RBP4 and hepatic fat accumulation. Fetuin-A acts as an endogenous ligand for TLR4 which stimulates adipose tissue inflammation and regulates insulin sensitivity [ 27 , 28 ]. The role of fetuin-A in the pathophysiology of insulin resistance in rodents was proved by studies conducted on Ahsg knockout mice KO [ 29 ]. The fetuin-A KO animals showed increased insulin signalling, sensitivity, and resistance to weight gain to the adipogenic effect of the HF.

    Remarkably, KO mice fed with HF remained lean, with body weight comparable to the control group [ 29 ]. Human studies show that fetuin-A plasma levels correlate positively with the liver fat accumulation in nondiabetic individuals, while Ahsg mRNA expression is upregulated in hepatic dysfunction [ 30 ].

    In a rat model of diet-induced obesity, which commonly displays fatty liver, an upregulation in Ahsg mRNA expression was also observed in the liver [ 12 ]. Under this conditions FGF21 acts in an autocrine fashion regulating liver fatty acid metabolism, promoting glucose utilization, and controlling peripheral glucose homeostasis by stimulating hepatic glycogen storage [ 34 , 35 ].

    These data led to the hypothesis that increased plasma FGF21 levels may be a prognostic factor of metabolic syndrome and T2DM and that these may be states of relative FGFresistance [ 37 ]. Similar results, but not related to the diet, were observed in human studies after laparoscopic sleeve gastrectomy, where FGF21 plasma levels in obese subjects were significantly higher in comparison to the control and decreased 12 and 24 months after the surgery [ 39 ].

    Other studies have shown that a very low-calorie diet applied for two weeks increased the FGF21 plasma levels in obese patients with T2DM [ 40 ]. Food restriction and low caloric diet appear to enhance hepatic FGF21 production, which helps to facilitate the physiological response to energy deficiency by reduction of gluconeogenesis and increase of hepatic ketogenesis via FGF21 [ 41 ].

    Nonetheless, the plasma concentration of FGF21 is also known to be elevated under conditions of metabolic dysfunction, such as obesity [ 40 ]. Our present results may explain an influence of DJOS surgery on the normalisation of the FGF21 sensitivity, which has been reported to be highly reduced under obesity conditions [ 35 ]. Downregulation of the Fgf21 mRNA expression after DJOS surgery may also suggest amelioration in the liver metabolic functions, since the liver may be responsible for the rise of the plasma FGF21 levels during overfeeding.

    These data demonstrate that manipulation of dietary patterns can lead to marked improvements in metabolic profile after DJOS surgery. The data used to support the findings of this study are available from the corresponding author upon request. All animal experimental protocols were approved by the Local Ethics Committee, Poland. The total amount of the compounds infused during each experiment was The experiments were performed in a randomized order.

    Low forearm blood flow. Intermediate forearm blood flow. High forearm blood flow. Venous blood samples 10 ml each were taken at five time-points: The total amount of blood taken from each volunteer was approximately ml.

    Heparinized blood samples for the determination of inulin were centrifuged for 10 min at g, and plasma was immediately separated. Plasma inulin was subsequently determined by a fully enzymatic method [12, 13]. The blood samples for the measurement of ICG were allowed to clot, and were subsequently centrifuged for 10 min at g, after which serum was separated immediately.

    A dye calibration curve was prepared from each subject's blank serum. Pre-infusion values were recorded during three min before each experiment. BP, from the six consecutive recordings before each sample, were used for analysis. Wilcoxon's signed rank test for matched pairs was used to evaluate the statistical significance of the data.

    P -values lower than 0. Calculated and measured plasma concentrations are presented according to the Bland—Altman method [14]. Logarithmic transformations were performed in order to obtain Gaussian distributions. The log-transformed average of the calculated and measured plasma concentrations were plotted on the abscissa, against the log-transformed difference between the two on the ordinate. Clinical and hemodynamic characteristics of the subjects are given in Table 1.

    Pre-infusion values of FBF established in the various experiments were all in the same range for both arms. In all experiments no statistically significant changes in HR or i. The baseline haemodynamic characteristics were obtained at least 45 min after cannulation of the brachial artery.

    The calculated concentrations of both inulin and ICG corresponded with the concentrations measured in the venous plasma, at all time-points. During the infusion with vehicle FBF remained constant 3.

    The calculated concentrations of ICG still displayed a strong correspondence with the concentrations measured in the venous plasma, at all time-points Fig. Bland-Altman analysis showed a high level of agreement between the calculated and measured plasma concentrations for both inulin and ICG. For inulin and ICG the differences in log-concentration were 0.

    Venous occlusion plethysmography of the forearm is widely used to indirectly assess the effects of intra-arterially infused vasoactive compounds on human peripheral resistance vessels see [1, 2]. In order to relate drug concentrations in arteriolar plasma to pharmacologic effects the following has to be considered.

    Plasma concentrations of the infused compounds can provide important information on their pharmacologic characteristics. Substances that are continuously infused into the brachial artery reach the resistance vessels almost instantaneously.

    In addition, as long as these compounds have not yet passed through the capillary bed, they have not penetrated the extravascular tissue compartment. Since concentrations cannot be measured at the arteriolar level directly, they either have to be calculated or estimated by measurement in venous blood samples. The latter approach, however, is laborious and often limited by technical problems.

    Also, venous plasma concentrations may not be representative for the actual concentration that exists at the arteriolar side of the vascular bed, since infused compounds may diffuse into the extravascular compartment. In our present investigations, this issue is illustrated by the discrepancy in the measured plasma concentrations of inulin as compared to ICG.

    It is taken up from the plasma almost exclusively by the hepatic parenchymal cells and is subsequently secreted entirely into the bile. ICG is clinically used for determining blood volume [10] , cardiac output [15] , hepatic function, liver and renal blood flow [16—18] , blood flow through mesenteric and peripheral arteries [19, 20] and hemodialysis fistulae [21]. In our experiments, the ICG plasma concentration calculated corresponded strongly with the concentrations measured in venous blood samples, at all time-points and at all blood flow levels.

    This can be explained by the fact that most of the ICG binds to plasma protein almost immediately after it has been infused, so that it is greatly inhibited to leave the vascular compartment. Inulin is an inert dalton uncharged polymer of fructose, which is clinically used for the determination of renal function by measurement of the glomerular filtration rate [22]. In contrast to ICG, inulin does not bind to plasma proteins and therefore can easily penetrate into the interstitial compartment when passing through the capillary bed.

    Therefore, its volume of distribution practically equals that of the extracellular compartment. Since the capillary extraction of inulin is rather flow independent see ref.

    In an organ system, the latter is determined by the product of blood flow and the extraction rate [23]. Therefore, with a constant infusion rate at low forearm blood flows it will take longer to reach equilibrium between the plasma and tissue compartments, than at high forearm blood flows. Our data are the first to show that over a wide range of flow conditions plasma concentrations of compounds infused intra-arterially into the vascular bed of the human forearm can be accurately estimated by calculation.

    The currently proposed approach, however, does not account for nonspecific loss of infused vasoactive compounds such as plasma protein binding, uptake or degradation mechanisms. The equation used provides an appropriate approximation of the total plasma concentrations of intra-arterially infused drugs at the level of the arterioles, considering the influence of variations in FBF. Furthermore, it indeed allows quantitative assessment of the pharmacologic characteristics of vasoactive compounds [6—9] , and the characterization of receptors by classical pharmacologic techniques, as we have demonstrated for muscarinic receptor subtypes [6, 8].

    Assessment of responses to drugs in forearm resistance vessels and hand veins of man: Kuhlmann J, Wingender W, editors.

    Dose-response relationship of drugs. Clinical pharmacology series, vol. Crone C, Levitt DG. Capillary permeability to small solutes. Handbook of physiology, Section 2, The cardiovascular system, Vol. Am Physiol Soc, Laboratory assessment of renal disease: Clearance, urinalysis, and renal biopsy.

    Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Close mobile search navigation Article navigation. Calculation of plasma concentrations of intra-arterially infused compounds in forearm plethysmography Tobias A Bruning. Pieter A van Zwieten. View large Download slide. Clinical and hemodynamic characteristics of the six male subjects studied.

    Measuring forearm blood flow and interpreting the responses to drugs and mediators. Calibration and variability of forearm blood flow, measured by strain gauge plethysmography.

    A microcomputer based R-wave triggered system for hemodynamic measurements in the forearm. In vivo characterization of vasodilating muscarinic-receptor subtypes in humans.


    Although nevirapine plasma concentrations were mg/l lower when .. shown that a plasma concentration of at least – mg/l is needed. for the E. coli method, but concentrations Plasma Concentrations. Compared to other drugs of abuse, analysis of. Diffusion is the movement of particles from an area of higher concentration to an (a) Facilitated diffusion of substances crossing the cell (plasma) membrane.

    1 Introduction



    Although nevirapine plasma concentrations were mg/l lower when .. shown that a plasma concentration of at least – mg/l is needed.


    for the E. coli method, but concentrations Plasma Concentrations. Compared to other drugs of abuse, analysis of.

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