scholarly journals Polyethylene glycol 400 (PEG400) affects the systemic exposure of oral drugs based on multiple mechanisms: taking berberine as an example

RSC Advances ◽  
2017 ◽  
Vol 7 (5) ◽  
pp. 2435-2442 ◽  
Author(s):  
Bing-Liang Ma ◽  
Yan Yang ◽  
Yan Dai ◽  
Qiao Li ◽  
Ge Lin ◽  
...  
Keyword(s):  
Polyethylene Glycol ◽  
Systemic Exposure ◽  
Lymphatic Transport ◽  
Oral Drugs ◽  
Polyethylene Glycol 400 ◽  
High Concentrations

High concentrations of PEG400 increase in vivo exposure to berberine (D) by increasing its solubility (A), permeability (B), and lymphatic transport (C).

scholarly journals Strawberry Decreases Intraluminal and Intestinal Wall Hydrolysis of Testosterone Undecanoate

Molecules ◽  
2021 ◽  
Vol 26 (1) ◽  
pp. 233
Author(s):  
Atheer Zgair ◽  
Yousaf Dawood ◽  
Suhaib M. Ibrahem ◽  
Jong Bong Lee ◽  
Wanshan Feng ◽  
...  
Keyword(s):  
Systemic Exposure ◽  
Inhibitory Effect ◽  
Intestinal Wall ◽  
Intestinal Lumen ◽  
Lymphatic Transport ◽  
Male Hypogonadism ◽  
Simulated Intestinal Fluid ◽  
Testosterone Undecanoate ◽  
Hydrolysis Of

Male hypogonadism is often treated by testosterone (T) replacement therapy such as oral administration of the ester prodrug, testosterone undecanoate (TU). However, the systemic exposure to T following oral TU is very low due to esterase-mediated metabolism, particularly in the small intestine. The aim of this work was to examine the esterase-inhibitory effect of natural fruit extract of strawberry (STW) on the intestinal degradation of TU as a potential approach to increasing the oral bioavailability of T. Herein, the hydrolysis of TU was assessed in fasted state simulated intestinal fluid with added esterase activity (FaSSIF/ES) and Caco-2 cell homogenates in the presence of STW extract. It is noteworthy that STW substantially inhibited the degradation of TU in FaSSIF/ES and Caco-2 cell homogenates at concentrations that could be achieved following oral consumption of less than one serving of STW fruit. This can significantly increase the fraction of unhydrolyzed TU in the intestinal lumen as well as in enterocytes. In addition, it was demonstrated that TU has high intestinal lymphatic transport potential as the association of TU with plasma-derived human chylomicrons was in the range of 84%. Therefore, oral co-administration of TU with STW could potentially increase the intestinal stability of TU and consequently the contribution of lymphatically delivered TU to the systemic exposure of T in vivo.

Diffusion of Polyethylene Glycol-400 across Lipid Barriers in Vitro

1993 ◽  
Vol 85 (1) ◽  
pp. 111-115 ◽  
Author(s):  
T. H. Iqbal ◽  
K. O. Lewis ◽  
B. T. Cooper
Keyword(s):  
Polyethylene Glycol ◽  
Petroleum Ether ◽  
Intestinal Permeability ◽  
Intestinal Wall ◽  
Water Soluble ◽  
Separate Experiment ◽  
Polyethylene Glycol 400 ◽  
Lipid Barriers

1. Polyethylene glycol has been used extensively as a probe to measure passive small-intestinal permeability in viro. However, there has been some uncertainty as to its suitability for use as an indicator of the permeation of water-soluble molecules across the intestinal wall because it seems to traverse the mucosa in much greater quantities than sugar molecules of equivalent Mr. 2. We have measured the permeation of polyethylene glycol-400 and lactulose from aqueous solution across pure lipid solvents in vitro. We found considerable transport of polyethylene glycol-400 across chloroform (1.03 g h−1 m−2) but no movement across petroleum ether. 3. However, in a separate experiment in which phospholipid (egg lecithin) was dissolved in the petroleum ether, permeation of polyethylene glycol-400 did occur (0.13 g h−1 m2), implying interaction of polyethylene glycol-400 with the phospholipid. No permeation of lactulose was seen in any of the experiments. 4. Our results suggest that, because of its interaction with lipid solvents, polyethylene glycol-400 is unsuitable as a probe to measure passive intestinal permeability in vivo.

scholarly journals The concentration of IgG in the serum is a major determinant of Fc- dependent reticuloendothelial function

Blood ◽  
1985 ◽  
Vol 66 (3) ◽  
pp. 490-495 ◽  
Author(s):  
JG Kelton ◽  
J Singer ◽  
C Rodger ◽  
J Gauldie ◽  
P Horsewood ◽  
...  
Keyword(s):  
Polyethylene Glycol ◽  
Immune Complexes ◽  
Fc Receptors ◽  
Secondary Effect ◽  
Macrophage Receptors ◽  
Healthy Control ◽  
Rapid Clearance ◽  
High Concentrations

Abstract Defective Fc receptor-specific reticuloendothelial (RE) function has been reported in certain patients with a variety of immunologic and nonimmunologic diseases. The mechanism responsible for the impaired RE function is uncertain, but it could be caused by immune complexes that are present in many of these disorders. Alternatively, the impaired RE function could be a secondary effect of the high concentrations of monomeric IgG in the serum of these patients, since monomeric IgG can compete with complexed IgG for macrophage receptors in vitro. We studied the Fc-dependent RE function in 30 healthy control subjects and 27 patients using IgG-coated radiolabeled autologous red cells. There was a significant relationship between the concentration of IgG in the serum and the rate of clearance of antibody-sensitized cells (r = 0.51, P less than .01). Patients with hypergammaglobulinemia had the slowest Fc-dependent clearance, whereas those with hypogammaglobulinemia had the most rapid clearance. Immune complexes (Raji or polyethylene glycol) could not be shown to contribute to Fc-dependent RE clearance above the effect of the IgG in the serum. The unusually rapid clearance in a patient with hypogammaglobulinemia could be returned to normal by raising the concentration of IgG in the serum. This study supports the concept that serum (monomeric) IgG competes with immune complexed IgG for macrophage Fc receptors in vivo. The competition for Fc receptors determines the level of competence of Fc-dependent RE function. Based on the results of this study, one can predict that a number of disorders characterized by hypergammaglobulinemia also will have impaired Fc-dependent RE function.

Study of biodegradation and biocompatibility of PEGylated rosin derivatives

2017 ◽  
Vol 32 (6) ◽  
pp. 628-640 ◽  
Author(s):  
Dinesh M Morkhade ◽  
Vishwanath S Nande ◽  
Umesh V Barabde ◽  
Siddheshwar B Joshi
Keyword(s):  
Molecular Weight ◽  
Weight Loss ◽  
Polyethylene Glycol ◽  
Inflammatory Responses ◽  
Tissue Response ◽  
Polyethylene Glycol 400 ◽  
Constant Weight ◽  
In Vivo Degradation

PEGylated rosin derivatives are improved in series ester-adduct derivatives of rosin. The aim of this study was to assess biodegradation and biocompatibility of PEGylated rosin derivatives. Study employed two different PEGylated rosin derivatives, namely, D1 and D2, with constant weight of rosin and increasing amounts of polyethylene glycol 400. PEGylated rosin derivatives were synthesized and tailored into spherical beads and disks with smooth surface for use. In vitro degradation was studied at pH 4.0, 7.4, and 10 for 60 days. In vivo study was performed in Wistar rats using poly(d,l-lactide- co-glycolide) (50:50) as a control. Post 3, 7, 14, and 21 days of implantation, PEGylated rosin derivatives disks were retrieved and evaluated for weight loss, molecular weight decline, morphology, and tissue response. D1 and D2 beads showed 21.68% and 32.37% weight loss, respectively, at pH 7.4 post 60 days. Degradation was increased substantially with increase in pH of medium. Degradation of disks was markedly slower than that of beads. In vivo degradation of PEGylated rosin derivative disks was faster than in vitro. Post 60 days of implantation, weight loss of D1 and D2 disk was 7.57% and 11.84%, whereas molecular weight was declined by about 19% and 26%, respectively. Owing to higher amounts of polyethylene glycol 400, in vitro and in vivo degradation of D2 was faster than D1. Poly(d,l-lactide- co-glycolide) as well as PEGylated rosin derivative implants evoked mild inflammatory responses characterized by few macrophages and absence of exudation at tissue–disk interface. The cellular density in tissue surrounding PEGylated rosin derivative disks increased initially with time up to 7 days and decreased eventually at the end of 21 days. The trend was similar for poly(d,l-lactide- co-glycolide) implants. Increase in polyethylene glycol 400 improved biodegradation and biocompatibility of PEGylated rosin derivatives. Results revealed that PEGylated rosin derivatives degrade slowly in vivo over a period of time, possess fair biocompatibility, and thus are promising biomaterial for drug delivery applications.

scholarly journals The concentration of IgG in the serum is a major determinant of Fc- dependent reticuloendothelial function

Blood ◽  
1985 ◽  
Vol 66 (3) ◽  
pp. 490-495
Author(s):  
JG Kelton ◽  
J Singer ◽  
C Rodger ◽  
J Gauldie ◽  
P Horsewood ◽  
...  
Keyword(s):  
Polyethylene Glycol ◽  
Immune Complexes ◽  
Fc Receptors ◽  
Secondary Effect ◽  
Macrophage Receptors ◽  
Healthy Control ◽  
Rapid Clearance ◽  
High Concentrations

Defective Fc receptor-specific reticuloendothelial (RE) function has been reported in certain patients with a variety of immunologic and nonimmunologic diseases. The mechanism responsible for the impaired RE function is uncertain, but it could be caused by immune complexes that are present in many of these disorders. Alternatively, the impaired RE function could be a secondary effect of the high concentrations of monomeric IgG in the serum of these patients, since monomeric IgG can compete with complexed IgG for macrophage receptors in vitro. We studied the Fc-dependent RE function in 30 healthy control subjects and 27 patients using IgG-coated radiolabeled autologous red cells. There was a significant relationship between the concentration of IgG in the serum and the rate of clearance of antibody-sensitized cells (r = 0.51, P less than .01). Patients with hypergammaglobulinemia had the slowest Fc-dependent clearance, whereas those with hypogammaglobulinemia had the most rapid clearance. Immune complexes (Raji or polyethylene glycol) could not be shown to contribute to Fc-dependent RE clearance above the effect of the IgG in the serum. The unusually rapid clearance in a patient with hypogammaglobulinemia could be returned to normal by raising the concentration of IgG in the serum. This study supports the concept that serum (monomeric) IgG competes with immune complexed IgG for macrophage Fc receptors in vivo. The competition for Fc receptors determines the level of competence of Fc-dependent RE function. Based on the results of this study, one can predict that a number of disorders characterized by hypergammaglobulinemia also will have impaired Fc-dependent RE function.

Hair cell changes after cationic stimulation of corti's organ

1989 ◽  
Vol 47 ◽  
pp. 798-799
Author(s):  
Cesar D. Fermin ◽  
Hans-Peter Zenner
Keyword(s):  
Organ Of Corti ◽  
Cross Sectional ◽  
Surface Areas ◽  
High K ◽  
Anatomical Arrangement ◽  
Cell Cytosol ◽  
High Concentrations ◽  
K Concentration ◽  
Cell Changes

Contraction of outer and inner hair cells (OHC&IHC) in the Organ of Corti (OC) of the inner ear is necessary for sound transduction. Getting at HC in vivo preparations is difficult. Thus, isolated HCs have been used to study OHC properties. Even though viability has been shown in isolated (iOHC) preparations by good responses to current and cationic stimulation, the contribution of adjoining cells can not be explained with iOHC preparations. This study was undertaken to examine changes in the OHC after expossure of the OHC to high concentrations of potassium (K) and sodium (Na), by carefully immersing the OC in either artifical endolymph or perilymph. After K and Na exposure, OCs were fixed with 3% glutaraldehyde, post-fixed in osmium, separated into base, middle and apex and embedded in Araldite™. One μm thick sections were prepared for analysis with the light and E.M. Cross sectional areas were measured with Bioquant™ software.Potassium and sodium both cause isolated guinea pig OHC to contract. In vivo high K concentration may cause uncontrolled and sustained contractions that could contribute to Meniere's disease. The behavior of OHC in the vivo setting might be very different from that of iOHC. We show here changes of the cell cytosol and cisterns caused by K and Na to OHC in situs. The table below shows results from cross sectional area measurements of OHC from OC that were exposed to either K or Na. As one would expect, from the anatomical arrangement of the OC, OHC#l that are supported by rigid tissue would probably be displaced (move) less than those OHC located away from the pillar. Surprisingly, cells in the middle turn of the cochlea changed their surface areas more than those at either end of the cochlea. Moreover, changes in surface area do not seem to differ between K and Na treated OCs.

STEROID METABOLISM IN THE PERFUSED HUMAN PLACENTA

1978 ◽  
Vol 87 (1) ◽  
pp. 181-191 ◽  
Author(s):  
Alfred S. Wolf ◽  
Klaus A. Musch ◽  
Werner Speidel ◽  
Jürgen R. Strecker ◽  
Christian Lauritzen
Keyword(s):  
Venous Blood ◽  
Placental Lactogen ◽  
Dehydroepiandrosterone Sulphate ◽  
Metabolic Capacity ◽  
Loading Test ◽  
Lower Range ◽  
Group I ◽  
High Concentrations ◽  
Steroid Precursor

ABSTRACT A new model for the perfusion of human term-placentas has been developed for studies on the placental biogenesis of C-18 and C-19 steroids. For viability criteria, the glucose- and oxygen-consumption, regional perfusion control by dye-infusions or scanning after injection of 99Tc-labelled macroparticles, and the histological qualification were chosen. The recycled perfusate was investigated for the steroids oestrone (Oe1), oestradiol-17β (Oe2), oestriol (Oe3), 4-androstene-3,17-dione (A), testosterone (T), and human placental lactogen (HPL) by radioimmunoassay in controls and perfusions with the foetal steroid precursor dehydroepiandrosterone sulphate (DHA-S). In control perfusions, steroid hormones were found in constant ratios (Oe1:Oe2:Oe3:T:A = 30:1.5:100:0.35:1). Following the administration of 10 mg DHA-S for testing the metabolic capacity of the organ, high concentrations of Oe1 (90–720 ng/ml = 250–3970 % as compared to 100% pre-injection values) were found, shortly preceded by a rapid increase of A (66–1000 ng/ml = 100–16 000 %). A typical surge of T (5.3–147 ng/ml = 265–4640 %) preceded the normally slower increment of Oe2 (22–220 ng/ml = 1570–4330 %). The concentrations of Oe3 and HPL remained nearly unchanged. From different steroid patterns after DHA-S-load, two distinct responses of term-placentas could be differentiated: Group I (n=12) showed high concentrations of Oe1 (3200 ± 940 %), a small increase of T (1020 ± 500%), as well as low and delayed values of Oe2 (1660 ± 450%). In Group II (n = 5), values were high for T (3160 ± 1020%) and Oe2 (3300 ± 1110%), whereas Oe1 was found in a lower range (508 ± 302%). In contrast to in vivo findings in maternal venous blood after DHS-S injection to the mother, oestrone was found in perfusions as the main oestrogen fraction from DHA-S. Thus, the analysis of such metabolic differences might be of help in the interpretation of complex results from the DHA-S-loading test.

The design, synthesis, pharmacokinetic and pharmacodynamic evaluation of acyloxyalkyl-substituted T705 prodrugs

2019 ◽  
Vol 15 ◽  
Author(s):  
Xingzhou Li ◽  
Tianhong Zhang ◽  
Wu Zhong
Keyword(s):  
Plasma Concentration ◽  
Development Strategy ◽  
Parent Compound ◽  
Systemic Exposure ◽  
Parent Drug ◽  
New Drugs ◽  
Structure Modification ◽  
Design Synthesis ◽  
Pharmacokinetic Properties

Background: The pharmacokinetic properties of T705 are not optimal for the development of new drugs. Objective: To improve the pharmacokinetic properties of T-705, structure modification of T-705 was conducted using a prodrug strategy. Method: The acidic amide H atom (N4-H) of T705 was attempted to be replaced with acyloxyalkyl groups following the prodrugs development strategy for carboxylic acids, and the resulting compounds were investigated whether could work as prodrugs and contribute to improving the pharmacokinetic properties of the parent compound T705 in vivo. Results: 4-acyloxyalkyl-T705 (4a–e), did act as prodrugs in vivo. 4-iso-butyryloxymethyl-T705 (4a) and 4-acetoxymethyl-T705 (4b) could significantly improve the plasma concentration and systemic exposure for T705, compound 4a displayed non inferior anti-influenza activities, compared with its parent drug T705. Conclusion: Our prodrugs development strategy for T705 is feasible, which may serves as a reference to prodrugs development of similar heterocyclic amides compounds.

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