scholarly journals Improved Pharmacokinetics and Tissue Uptake of Complexed Daidzein in Rats

Pharmaceutics ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 162
Author(s):  
Anna Kwiecień ◽  
Jana Ruda-Kucerova ◽  
Kamil Kamiński ◽  
Zuzana Babinska ◽  
Iwona Popiołek ◽  
...  
Keyword(s):  
Inclusion Complex ◽  
Intraperitoneal Administration ◽  
Fold Increase ◽  
Relative Bioavailability ◽  
Absolute Bioavailability ◽  
Rat Tissues ◽  
Tissue Uptake ◽  
Rat Serum ◽  
Eda Complex ◽  
The Absolute

The pharmacokinetic profile and tissue uptake of daidzein (DAI) was determined in rat serum and tissues (lungs, eyes, brain, heart, spleen, fat, liver, kidney, and testes) after intravenous and intraperitoneal administration of DAI in suspension or complexed with ethylenediamine-modified γ-cyclodextrin (GCD-EDA/DAI). The absolute and relative bioavailability of DAI suspended (20 mg/kg i.v. vs. 50 mg/kg i.p.) and complexed (0.54 mg/kg i.v. vs. 1.35 mg/kg i.p.) was determined. After i.p. administration, absorption of DAI complexed with GCD-EDA was more rapid (tmax = 15 min) than that of DAI in suspension (tmax = 45 min) with a ca. 3.6 times higher maximum concentration (Cmax = 615 vs. 173 ng/mL). The i.v. half-life of DAI was longer in GCD-EDA/DAI complex compared with DAI in suspension (t0.5 = 380 min vs. 230 min). The volume of distribution of DAI given i.v. in GCD-EDA/DAI complex was ca. 6 times larger than DAI in suspension (38.6 L/kg vs. 6.2 L/kg). Our data support the concept that the pharmacokinetics of DAI suspended in high doses are nonlinear. Increasing the intravenous dose 34 times resulted in a 5-fold increase in AUC. In turn, increasing the intraperitoneal dose 37 times resulted in a ca. 2-fold increase in AUC. The results of this study suggested that GCD-EDA complex may improve DAI bioavailability after i.p. administration. The absolute bioavailability of DAI in GCD-EDA inclusion complex was ca. 3 times greater (F = 82.4% vs. 28.2%), and the relative bioavailability was ca. 21 times higher than that of DAI in suspension, indicating the need to study DAI bioavailability after administration by routes other than intraperitoneal, e.g., orally, subcutaneously, or intramuscularly. The concentration of DAI released from GCD-EDA/DAI inclusion complex to all the rat tissues studied was higher than after administration of DAI in suspension. The concentration of DAI in brain and lungs was found to be almost 90 and 45 times higher, respectively, when administered in complex compared to the suspended DAI. Given the nonlinear relationship between DAI bioavailability and the dose released from the GCD-EDA complex, complexation of DAI may thus offer an effective approach to improve DAI delivery for treatment purposes, for example in mucopolysaccharidosis (MPS), allowing the reduction of ingested DAI doses.

scholarly journals ABSOLUTE AND RELATIVE BIOAVAILABILITY STUDY FOR THE NEWLY DEVELOPED NASAL NANOEMULSION IN SITU GEL OF ONDANSETRON HCl IN COMPARISON TO CONVENTIONALLY PREPARED IN SITU GEL AND INTRAVENOUS DOSAGES FORMS

2018 ◽  
Vol 10 (5) ◽  
pp. 105
Author(s):  
Nidhal K. Maraie ◽  
Yasser Q. Almajidi ◽  
Ahmed Alshadher
Keyword(s):  
Relative Bioavailability ◽  
The Body ◽  
Absolute Bioavailability ◽  
Pharmacokinetic Studies ◽  
Bioavailability Enhancement ◽  
In Situ Gel ◽  
Bioavailability Study ◽  
The Absolute

Objective: The aim of the work was to study the absolute and relative bioavailability (using rabbits) of ondansetron HCl (ONH)from our newly prepared intranasal mucoadhesive nanoemulsion in situ gel (NIG) in comparison to intranasal mucoadhesive in situ gel (IG) prepared by the conventional method and intravenous injection.Methods: Six male rabbits weighing 2.5-3 kg were used in this study, where the dose of ondansetron HCl (ONH) was calculated based on the body surface area (BSA) which is equivalent to 140μl (containing 10 mg/ml) of NIG and IG and 700μl of intravenous Zofran® injection (containing 2 mg/ml) were given to the rabbits, separated with one week washout period. Serial blood samples were withdrawn and analyzed for simultaneous determination of the drug using HPLC (Knaure; 150 ×4.6 mm; 5 μm particle size; 25 cm length) supported by guard column C18-4 mm diameter.Results: The pharmacokinetics parameters for NIG; Cmax, Tmax, AUC0-t, AUC0-∞were found to be greater than conventional in situ gel (IG). In vivo pharmacokinetic studies in rabbits showed a significant increase in Cmax and AUC 0-α(P<0.001) with shorter Tmaxusing NIG compared to IG containing the same NIG excipients, while the absolute bioavailability for NIG and IG (was 80.541 and 51.068 respectively).Conclusion: The present studies ratify the bioavailability enhancement potential of NE used to prepare NIG for the drug and significantly high absolute bioavailability to be used as a successful alternative route to the IV injection and improve patient compliance.

scholarly journals A Role for Xanthurenic Acid in the Control of Brain Dopaminergic Activity

2021 ◽  
Vol 22 (13) ◽  
pp. 6974
Author(s):  
Omar Taleb ◽  
Mohammed Maammar ◽  
Christian Klein ◽  
Michel Maitre ◽  
Ayikoe Guy Mensah-Nyagan
Keyword(s):  
Dopamine Release ◽  
Intraperitoneal Administration ◽  
Glutamate Transporter ◽  
Fold Increase ◽  
Xanthurenic Acid ◽  
Metabotropic Receptors ◽  
Parent Molecule ◽  
Dopaminergic Activity ◽  
The Brain

Xanthurenic acid (XA) is a metabolite of the kynurenine pathway (KP) synthetized in the brain from dietary or microbial tryptophan that crosses the blood-brain barrier through carrier-mediated transport. XA and kynurenic acid (KYNA) are two structurally related compounds of KP occurring at micromolar concentrations in the CNS and suspected to modulate some pathophysiological mechanisms of neuropsychiatric and/or neurodegenerative diseases. Particularly, various data including XA cerebral distribution (from 1 µM in olfactory bulbs and cerebellum to 0.1–0.4 µM in A9 and A10), its release, and interactions with G protein-dependent XA-receptor, glutamate transporter and metabotropic receptors, strongly support a signaling and/or neuromodulatory role for XA. However, while the parent molecule KYNA is considered as potentially involved in neuropsychiatric disorders because of its inhibitory action on dopamine release in the striatum, the effect of XA on brain dopaminergic activity remains unknown. Here, we demonstrate that acute local/microdialysis-infusions of XA dose-dependently stimulate dopamine release in the rat prefrontal cortex (four-fold increase in the presence of 20 µM XA). This stimulatory effect is blocked by XA-receptor antagonist NCS-486. Interestingly, our results show that the peripheral/intraperitoneal administration of XA, which has been proven to enhance intra-cerebral XA concentrations (about 200% increase after 50 mg/kg XA i.p), also induces a dose-dependent increase of dopamine release in the cortex and striatum. Furthermore, our in vivo electrophysiological studies reveal that the repeated/daily administrations of XA reduce by 43% the number of spontaneously firing dopaminergic neurons in the ventral tegmental area. In the substantia nigra, XA treatment does not change the number of firing neurons. Altogether, our results suggest that XA may contribute together with KYNA to generate a KYNA/XA ratio that may crucially determine the brain normal dopaminergic activity. Imbalance of this ratio may result in dopaminergic dysfunctions related to several brain disorders, including psychotic diseases and drug dependence.

Urinary excretion of the TRH-like peptide pyroglutamyl-glutamyl-prolineamide in rats

1997 ◽  
Vol 153 (3) ◽  
pp. 411-421 ◽  
Author(s):  
W Klootwijk ◽  
R D H de Boer ◽  
E Sleddens-Linkels ◽  
S M Cockle ◽  
W W de Herder ◽  
...  
Keyword(s):  
Urinary Excretion ◽  
Anterior Pituitary ◽  
Anion Exchange Chromatography ◽  
Exchange Chromatography ◽  
Female Rats ◽  
Male Rats ◽  
Rat Tissues ◽  
Rat Serum ◽  
Methanolic Extracts ◽  
Gonadotrophin Secretion

Abstract TRH-like immunoreactivity (TRH-LI) was estimated in methanolic extracts of rat tissues and blood by RIA using antiserum 4319, which binds most peptides with the structure pGlu-X-ProNH2, or antiserum 8880, which is specific for TRH (pGlu-His-ProNH2). TRH-LI (determined with antiserum 4319) and TRH (determined with antiserum 8880) contents were 8 and 8 ng/g in brain, 216 and 222 ng/g in hypothalamus, 6·5 and 6 ng/g in pancreas, 163 and 116 ng/g in male pituitary, 105 and 77 ng/g in female pituitary, 1 and 0·1 ng/g in salivary gland, 61 and 42 ng/g in thyroid, 12 and 3 ng/g in adrenal, 3 and 0·3 ng/g in prostate, and 11 and 0·8 ng/g in ovary respectively. Blood TRH-LI (antiserum 4319) and TRH (antiserum 8880) levels were 31 and 18 pg/ml in male rats, and 23 and 10 pg/ml in female rats respectively. Unextracted serum obtained from blood kept for at least 1 h at room temperature no longer contained authentic TRH but still contained TRH-LI (males 20·3 ± 3·1, females 15·9 ± 3·0 pg/ml; means ± s.e.m.). Isocratic reverse-phase HPLC showed that TRH-LI in serum is largely pGlu-Glu-ProNH2 (<EEP-NH2), a peptide previously found in prostate and anterior pituitary. In urine, TRH-LI (antiserum 4319) and TRH (antiserum 8880) levels were 3·21 ± 0·35 and 0·32 ± 0·04 ng/ml in male rats and 3·75 ± 0·22 and 0·37 ± 0·04 ng/ml in female rats respectively (means ± s.e.m.). Anion-exchange chromatography on QAE-Sephadex showed that urine of normally fed rats contains both basic/neutral TRH-LI (b/nTRH-LI) and acidic TRH-LI (aTRH-LI) in a ratio of ≈ 40:60, and further analysis by HPLC indicated that aTRH-LI represents <EEP-NH2. Analysis of food extracts and urine from fasted rats demonstrated that b/nTRH-LI is derived from food particles spilled by the rats during urine collection, while aTRH-LI is endogenously produced. While urinary aTRH-LI levels were higher in female than in male rats (2·99 ± 0·41 vs 2·04 ± 0·20 ng/ml), the daily urinary excretion was similar in both sexes (females 15·6 ± 1·4, males 19·5 ± 2·0 ng/day). Intravenously injected <EEP-NH2 disappeared from serum with a half-life of ≈ 1 h, and was recovered unchanged and quantitatively in urine. In contrast, when <EEP-NH2 was administered with food, only ≈ 0·5% was recovered in urine. The urinary clearance rate of serum TRH-LI amounted to 0·52 ± 0·10 ml/min in males and 0·34 ± 0·05 ml/min in females. In view of the presence of <EEP-NH2 in the anterior pituitary gland, and the regulation of its content in parallel with gonadotrophins, we examined the possibility that serum <EEP-NH2 is of pituitary origin and correlates with gonadotrophin secretion. However, treatments that alter pituitary <EEP-NH2 content and gonadotrophin release had no effect on serum TRH-LI or urinary aTRH-LI. In conclusion, the TRH-like peptide <EEP-NH2 is present in rat serum and is excreted into the urine. Moreover, <EEP-NH2 in serum and urine is not derived from rat food and is probably not of pituitary origin. Journal of Endocrinology (1997) 153, 411–421

scholarly journals Rat lung lectin synthesis, degradation and activation. Developmental regulation and modulation by dexamethasone

1987 ◽  
Vol 245 (3) ◽  
pp. 683-690 ◽  
Author(s):  
L B Clerch ◽  
P L Whitney ◽  
D Massaro
Keyword(s):  
Binding Protein ◽  
Developmental Regulation ◽  
Fold Increase ◽  
Rat Lung ◽  
Absolute Rate ◽  
Lectin Activity ◽  
Developmentally Regulated ◽  
Rat Pups ◽  
The Absolute

Soluble lectins are widely distributed cell-agglutinating proteins. Their activity is developmentally regulated in several tissues, including the lung, but virtually nothing is known about the mechanisms of the developmental regulation or the turnover of these proteins. We studied mechanisms that might be responsible for the developmentally regulated changes in the activity of a lectin (beta-galactoside-binding protein) found in the lung, and determined if its activity or turnover could be modulated by treatment of rat pups with a glucocorticosteroid hormone (dexamethasone). Our studies on the activity and turnover of the lectin indicated that the peak of lectin activity (units/mg of protein) that occurred at age 12 days appeared to be brought about by two means: an increase in the activity of the lectin molecule itself (units/micrograms of lectin) that occurred at age 8 days, and 1.5-fold increase in the absolute rate of lectin synthesis at age 11 days. The decline in lectin activity was associated with a decrease in its rate of synthesis, return to the baseline extent of activation, and an increased rate of degradation. Treatment of rat pups with dexamethasone diminished the peak of lectin activity (units/mg of protein) by about 25%. This effect of dexamethasone was due, at least in part, to the complete prevention of activation of the lectin molecule (units/micrograms of lectin) and a premature increase in the rate of lectin degradation. Perhaps the normal fall in lectin activity after age 11 days is caused by mechanisms induced by the increase in serum corticosteroid that occurs at that age.

scholarly journals Preparation, Characterization, and Bioavailability of Host-Guest Inclusion Complex of Ginsenoside Re with Gamma-Cyclodextrin

Molecules ◽  
2021 ◽  
Vol 26 (23) ◽  
pp. 7227
Author(s):  
Hui Li ◽  
Guolei Zhang ◽  
Wei Wang ◽  
Changbao Chen ◽  
Lili Jiao ◽  
...  
Keyword(s):  
Inclusion Complex ◽  
Water Solubility ◽  
Area Under The Curve ◽  
Relative Bioavailability ◽  
Docking Studies ◽  
Solubility Parameters ◽  
Phase Solubility ◽  
Scanning Calorimetry ◽  
Ginsenoside Re

This work aimed at improving the water solubility of Ginsenoside (G)-Re by forming an inclusion complex. The solubility parameters of G-Re in alpha (α), beta (β), and gamma (γ) cyclodextrin (CD) were investigated. The phase solubility profiles were all classified as AL-type that indicated the 1:1 stoichiometric relationship with the stability constants Ks which were 22 M−1 (α-CD), 612 M−1 (β-CD), and 14,410 M−1 (γ-CD), respectively. Molecular docking studies confirmed the results of phase solubility with the binding energy of −4.7 (α-CD), −5.10 (β-CD), and −6.70 (γ-CD) kcal/mol, respectively. The inclusion complex (IC) of G-Re was prepared with γ-CD via the water-stirring method followed by freeze-drying. The successful preparation of IC was confirmed by powder X-ray diffraction (XRD), Fourier transform-infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), and scanning electron microscopy (SEM). In-vivo absorption studies were carried out by LC-MS/MS. Dissolution rate of G-Re was increased 9.27 times after inclusion, and the peak blood concentration was 2.7-fold higher than that of pure G-Re powder. The relative bioavailability calculated from the ratio of Area under the curve AUC0–∞ of the inclusion to pure G-Re powder was 171%. This study offers the first report that describes G-Re’s inclusion into γ-CD, and explored the inclusion complex’s mechanism at the molecular level. The results indicated that the solubility could be significantly improved as well as the bioavailability, implying γ-CD was a very suitable inclusion host for complex preparation of G-Re.

Intermittent, Repetitive Corticosteroid-Induced Upregulation of Platelet Levels After Adenovirus-Mediated Transfer to the Liver of a Chimeric Glucocorticoid-Responsive Promoter Controlling the Thrombopoietin cDNA

Blood ◽  
1998 ◽  
Vol 92 (3) ◽  
pp. 822-833 ◽  
Author(s):  
Ko Narumi ◽  
Motoyoshi Suzuki ◽  
Wenru Song ◽  
Malcolm A.S. Moore ◽  
Ronald G. Crystal
Keyword(s):  
Clinical Medicine ◽  
Intraperitoneal Administration ◽  
Fold Increase ◽  
Inducible Promoter ◽  
Pharmacologic Agent ◽  
Before And After ◽  
American Society ◽  
Pharmacologic Agents

Abstract For many in vivo gene therapy clinical applications, it is desirable to control the expression of the transferred transgene using pharmacologic agents. To evaluate the feasibility of accomplishing this using corticosteroids, pharmacologic agents widely used in clinical medicine, we constructed replication deficient adenoviral (Ad) vectors containing an expression cassette with a chimeric promoter comprised of five glucocorticoid response elements (GRE) and the chloramphenicol acetyltransferase reporter gene (AdGRE.CAT) or the murine thrombopoietin cDNA (AdGRE.mTPO). In vitro studies showed the vectors functioned as expected, with marked glucocorticoid-induced upregulation of the CAT or mTPO transgenes. To evaluate the inducibility of the GRE promoter in vivo, the AdGRE.CAT vector was administered intravenously to C57B1/6 mice, and CAT activity was quantified in liver before and after intraperitoneal administration of dexamethasone. The GRE promoter activity was dependent on the dexamethasone dose, with a 100-fold increase in CAT expression with 50 μg dexamethasone, similar to the levels observed in vivo with the Rous sarcoma virus long terminal repeat constitutive promoter. After dexamethasone administration, maximum CAT activity was observed at day 2, with a slow decline to baseline levels by 2 weeks. Based on these observations, we hypothesized that a single administration of an Ad vector-mediated transfer of the chimeric GRE inducible promoter driving the mTPO cDNA would enable repetitive administration of corticosteroids to repetitively upregulate platelet levels for 1 to 2 weeks. The data show that this occurs, with dexamethasone administration every 3 weeks associated with 1-week elevations (at each 3-week interval) of serum mTPO levels, megakaryocyte numbers in bone marrow, and platelet levels fourfold to sixfold over baseline. Thus, with the appropriate promoter, it is possible to use a commonly used pharmacologic agent to upregulate the expression of a newly transferred gene on demand. © 1998 by The American Society of Hematology.

scholarly journals Nasal Administration and Plasma Pharmacokinetics of Parathyroid Hormone Peptide PTH 1-34 for the Treatment of Osteoporosis

Pharmaceutics ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 265 ◽  
Author(s):  
Richard G. Pearson ◽  
Tahir Masud ◽  
Elaine Blackshaw ◽  
Andrew Naylor ◽  
Michael Hinchcliffe ◽  
...  
Keyword(s):  
Nasal Spray ◽  
Subcutaneous Injection ◽  
Relative Bioavailability ◽  
Nasal Delivery ◽  
Absolute Bioavailability ◽  
Preclinical Model ◽  
Permeation Enhancer ◽  
Treatment Of Osteoporosis ◽  
Plasma Pharmacokinetics ◽  
Spray Formulation

Nasal delivery of large peptides such as parathyroid 1-34 (PTH 1-34) can benefit from a permeation enhancer to promote absorption across the nasal mucosa into the bloodstream. Previously, we have published an encouraging bioavailability (78%), relative to subcutaneous injection in a small animal preclinical model, for a liquid nasal spray formulation containing the permeation enhancer polyethylene glycol (15)-hydroxystearate (Solutol® HS15). We report here the plasma pharmacokinetics of PTH 1-34 in healthy human volunteers receiving the liquid nasal spray formulation containing Solutol® HS15. For comparison, data for a commercially manufactured teriparatide formulation delivered via subcutaneous injection pen are also presented. Tc-99m-DTPA gamma scintigraphy monitored the deposition of the nasal spray in the nasal cavity and clearance via the inferior meatus and nasopharynx. The 50% clearance time was 17.8 min (minimum 10.9, maximum 74.3 min). For PTH 1-34, mean plasma Cmax of 5 pg/mL and 253 pg/mL were obtained for the nasal spray and subcutaneous injection respectively; relative bioavailability of the nasal spray was ≤1%. Subsequently, we investigated the pharmacokinetics of the liquid nasal spray formulation as well as a dry powder nasal formulation also containing Solutol® HS15 in a crossover study in an established ovine model. In this preclinical model, the relative bioavailability of liquid and powder nasal formulations was 1.4% and 1.0% respectively. The absolute bioavailability of subcutaneously administered PTH 1-34 (mean 77%, range 55–108%) in sheep was in agreement with published human data for teriparatide (up to 95%). These findings have important implications in the search for alternative routes of administration of peptides for the treatment of osteoporosis, and in terms of improving translation from animal models to humans.

Metabolism of n-hexane by rat liver and extrahepatic tissues and the effect of cytochrome P-450 inducers

1997 ◽  
Vol 16 (3) ◽  
pp. 131-137 ◽  
Author(s):  
Sarah J Crosbie ◽  
PG Blain ◽  
Faith M Williams
Keyword(s):  
Skeletal Muscle ◽  
Rat Liver ◽  
Fold Increase ◽  
Rat Tissues ◽  
Human Cytochrome ◽  
Extrahepatic Tissues ◽  
Mass Spectometry ◽  
Fast Twitch ◽  
Cytochrome P 450

1 The in vitro metabolism ofn-hexane was studied in rat liver, lung, brain and skeletal muscle microsomes and in microsomes prepared from cell lines expressing human cytochrome P-450 2E1 or 2B6. The hydro xylated metabolites ofn-hexane were quantified by gas chromatography-mass spectometry. 2 Rat liver and extensor digitorum longus (EDL, fast- twitch skeletal muscle) microsomes and the CYP 2B6 microsomes produced the pre-neurotoxic metabolite of n-hexane, 2-hexanol as a major metabolite in contrast to the other rat tissues examined. 3 Inhibition of 2- and 3-hexanol production from n- hexane by rat lung microsomes using metyrapone, an inhibitor of cytochrome P-450 2B1 activity, resulted in almost complete inhibition of lung microsomal activ ity. 4 Production of all three hexanols was significantly increased with phenobarbital-induced rat liver micro somes, with a 10-fold increase in 2- and 3-hexanol production. A slight increase in 2-hexanol production with phenobarbital-induced rat EDL and brain micro somes was observed. No increase in n-hexane meta bolism was noted following induction with β- naphthoflavone or with ethanol.

Sign in / Sign up

Export Citation Format

Share Document