scholarly journals Pharmacokinetics of Amino Acid Phosphoramidate Monoesters of Zidovudine in Rats

2002 ◽  
Vol 46 (5) ◽  
pp. 1357-1363 ◽  
Author(s):  
Heng Song ◽  
George W. Griesgraber ◽  
Carston R. Wagner ◽  
Cheryl L. Zimmerman
Keyword(s):  
Amino Acid ◽  
High Performance ◽  
Volume Of Distribution ◽  
Water Soluble ◽  
Pharmacokinetic Parameters ◽  
Sprague Dawley ◽  
Binding Studies ◽  
Total Body

ABSTRACT In vitro studies have demonstrated that water-soluble, nontoxic phosphoramidates of azidothymidine (zidovudine [AZT]) have significant and specific anti-human immunodeficiency virus and anticancer activity. Although polar, these compounds are internalized and processed to the corresponding nucleoside monophosphates. Eight methyl amide and methyl ester phosphoramidate monoesters composed of d- or l-phenylalanine or tryptophan and AZT were synthesized. The plasma stability and protein binding studies were carried out in vitro. Then in vivo pharmacokinetic evaluations of six of the compounds were conducted. Sprague-Dawley rats received each compound by intravenous bolus dose, and serial blood and urine samples were collected. AZT and phosphoramidate concentrations in plasma and urine were quantitated by high-performance liquid chromatography with UV or fluorescence detection. Pharmacokinetic parameters were calculated by standard noncompartmental means. The plasma half-lives of the phosphoramidates were 10- to 20-fold longer than the half-life of AZT. Although the renal clearances of the phosphoramidates were similar to AZT, their total body clearances were significantly greater than that of AZT. The 3- to 15-fold-larger volume of distribution (V ss) for the phosphoramidates relative to AZT appeared to be dependent on the stereochemistry of the amino acid, with the largest values being associated with the l-amino acids. The increased V ss indicates a much greater tissue distribution of the phosphoramidate prodrugs than of AZT. Amino acid phosphoramidate monoesters of AZT have improved pharmacokinetic properties over AZT and significant potential as in vivo pronucleotides.

scholarly journals Pharmacokinetics of danofloxacin in African catfish (Clarias gariepinus) after intravenous and intramuscular administrations

2019 ◽  
Vol 67 (4) ◽  
pp. 602-609
Author(s):  
Mohamed Aboubakr ◽  
Ahmed Soliman
Keyword(s):  
Bacterial Infections ◽  
High Performance ◽  
Clarias Gariepinus ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
African Catfish ◽  
Caudal Vein ◽  
Group 2 ◽  
Total Body ◽  
The Right

The plasma pharmacokinetics of danofloxacin was studied in healthy African catfish (Clarias gariepinus) following a single intravenous (IV) and intramuscular (IM) administration of 10 mg/kg at 22 °C. Catfish were divided into two groups (each group containing 78 fish), then danofloxacin mesylate (10 mg/kg) was administered IV (into the caudal vein) in Group 1 and IM (into the right epaxial muscle) in Group 2, and blood was obtained from the caudal vein before (0 h) and after (0.25, 0.5, 1, 2, 4, 8, 12, 24, 36, 48, 72 and 96 h) of drug administration. High-performance liquid chromatography was used for the determination of plasma concentration, and a non-compartmental model was used for the analysis of pharmacokinetic parameters. After IV administration, elimination half-life (t1/2λz, 24.49 h), mean residence time (MRT, 30.14 h), volume of distribution at steady state (Vdss, 1.07 L/kg) and total body clearance (CLT, 0.035 L/h/kg) were determined. After IM administration, t1/2λz, MRT, peak concentration (Cmax), time to reach Cmax and bioavailability were 47.64 h, 61.06 h, 5.22 µg/mL, 1 h and 67.12%, respectively. After IM administration, danofloxacin showed good bioavailability and long t1/2λz. The favourable pharmacokinetic characteristics after IM administration support the use of danofloxacin for the treatment of susceptible bacterial infections in catfish.

Highly water-soluble derivatives of the anesthetic agent propofol: in vitro and in vivo evaluation of cyclic amino acid esters

2003 ◽  
Vol 20 (1) ◽  
pp. 17-26 ◽  
Author(s):  
Cosimo Altomare ◽  
Giuseppe Trapani ◽  
Andrea Latrofa ◽  
Mariangela Serra ◽  
Enrico Sanna ◽  
...  
Keyword(s):  
Amino Acid ◽  
Water Soluble ◽  
Anesthetic Agent ◽  
Amino Acid Esters ◽  
In Vivo Evaluation ◽  
Derivatives Of ◽  
Acid Esters

scholarly journals Comprehensive physicochemical, pharmacokinetic and activity profiling of anti-TB agents

2014 ◽  
Vol 70 (3) ◽  
pp. 857-867 ◽  
Author(s):  
Suresh B. Lakshminarayana ◽  
Tan Bee Huat ◽  
Paul C. Ho ◽  
Ujjini H. Manjunatha ◽  
Véronique Dartois ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Volume Of Distribution ◽  
Metabolic Stability ◽  
New Drugs ◽  
Pharmacokinetic Parameters ◽  
Lipinski’S Rule ◽  
Drug Classes ◽  
Human Pharmacokinetic

Abstract Objectives The discovery and development of TB drugs has met limited success, with two new drugs approved over the last 40 years. Part of the difficulty resides in the lack of well-established in vitro or in vivo targets of potency and physicochemical and pharmacokinetic parameters. In an attempt to benchmark and compare such properties for anti-TB agents, we have experimentally determined and compiled these parameters for 36 anti-TB compounds, using standardized and centralized assays, thus ensuring direct comparability across drugs and drug classes. Methods Potency parameters included growth inhibition, cidal activity against growing and non-growing bacteria and activity against intracellular mycobacteria. Pharmacokinetic parameters included basic physicochemical properties, solubility, permeability and metabolic stability. We then attempted to establish correlations between physicochemical, in vitro and in vivo pharmacokinetic and pharmacodynamic indices to tentatively inform future drug discovery efforts. Results Two-thirds of the compounds tested showed bactericidal and intramacrophage activity. Most compounds exhibited favourable solubility, permeability and metabolic stability in standard in vitro pharmacokinetic assays. An analysis of human pharmacokinetic parameters revealed associations between lipophilicity and volume of distribution, clearance, plasma protein binding and oral bioavailability. Not surprisingly, most compounds with favourable pharmacokinetic properties complied with Lipinski's rule of five. Conclusions However, most attempts to detect in vitro–in vivo correlations were unsuccessful, emphasizing the challenges of anti-TB drug discovery. The objective of this work is to provide a reference dataset for the TB drug discovery community with a focus on comparative in vitro potency and pharmacokinetics.

scholarly journals Comparative Evaluation of the Cytotoxicity of Glyphosate-Based Herbicides and Glycine in L929 and Caco2 Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Francesca Truzzi ◽  
Daniele Mandrioli ◽  
Federica Gnudi ◽  
Paul T. J. Scheepers ◽  
Ellen K. Silbergeld ◽  
...  
Keyword(s):  
Amino Acid ◽  
Trypan Blue ◽  
Intestinal Microbiome ◽  
Sprague Dawley ◽  
Literature Report ◽  
Cytotoxic Effects ◽  
Caco2 Cells ◽  
Ic50 Value

Introduction: Glyphosate, an amino acid analog of glycine, is the most widely applied organophosphate pesticide worldwide and it is an active ingredient of all glyphosate-based herbicides (GBHs), including the formulation “Roundup. ” While glycine is an essential amino acid generally recognized safe, both epidemiological and toxicological in vivo and in vitro studies available in literature report conflicting findings on the toxicity of GBHs. In our earlier in vivo studies in Sprague–Dawley rats we observed that exposure to GBHs at doses of glyphosate of 1.75 mg/kg bw/day, induced different toxic effects relating to sexual development, endocrine system, and the alteration of the intestinal microbiome. In the present work, we aimed to comparatively test in in vitro models the cytotoxicity of glycine and GBHs.Methods: We tested the cytotoxic effects of glycine, glyphosate, and its formulation Roundup Bioflow at different doses using MTT and Trypan Blue assays in human Caco2 and murine L929 cell lines.Results: Statistically significant dose-related cytotoxic effects were observed in MTT and Trypan Blue assays in murine (L929) and human (Caco2) cells treated with glyphosate or Roundup Bioflow. No cytotoxic effects were observed for glycine. In L929, Roundup Bioflow treatment showed a mean IC50 value that was significantly lower than glyphosate in both MTT and Trypan Blue assays. In Caco2, Roundup Bioflow treatment showed a mean IC50 value that was significantly lower than glyphosate in the MTT assays, while a comparable IC50 was observed for glyphosate and Roundup Bioflow in Trypan Blue assays. IC50 for glycine could not be estimated because of the lack of cytotoxic effects of the substance.Conclusion: Glyphosate and its formulation Roundup Bioflow, but not glycine, caused dose-related cytotoxic effects in in vitro human and murine models (Caco2 and L929). Our results showed that glycine and its analog glyphosate presented different cytotoxicity profiles. Glyphosate and Roundup Bioflow demonstrate cytotoxicity similar to other organophosphate pesticides (malathion, diazinon, and chlorpyriphos).

scholarly journals Formulation, In Vitro and In Vivo Evaluation of Gefitinib Solid Dispersions Prepared Using Different Techniques

Processes ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 1210
Author(s):  
Sultan Alshehri ◽  
Abdullah Alanazi ◽  
Ehab M. Elzayat ◽  
Mohammad A. Altamimi ◽  
Syed S. Imam ◽  
...  
Keyword(s):  
Oral Absorption ◽  
Solid Dispersions ◽  
Water Soluble ◽  
In Vitro Dissolution ◽  
Pharmacokinetic Parameters ◽  
Pharmacokinetic Studies ◽  
In Vivo Evaluation ◽  
Significant Release

Gefitinib (Gef) is a poorly water-soluble antitumor drug, which shows poor absorption/bioavailability after oral administration. Therefore, this study was carried out to develop Gef solid dispersions (SDs) using different carriers and different techniques in order to enhance its dissolution and oral absorption/bioavailability. Various SD formulations of Gef were established using fusion and microwave methods utilizing Soluplus, Kollidone VA64, and polyethylene glycol 4000 (PEG 4000) as the carriers. Developed SDs of Gef were characterized physicochemically and evaluated for in vitro dissolution and in vivo pharmacokinetic studies. The physicochemical evaluation revealed the formation of Gef SDs using fusion and microwave methods. In vitro dissolution studies indicated significant release of Gef from all SDs compared to the pure Gef. Optimized SD of Gef (S2-MW) presented significant release of Gef (82.10%) compared with pure Gef (21.23%). The optimized Gef SD (S2) was subjected to in vivo pharmacokinetic evaluation in comparison with pure Gef in rats. The results indicated significant enhancement in various pharmacokinetic parameters of Gef from an optimized SD S2 compared to the pure Gef. In addition, Gef-SD S2 resulted in remarkable improvement in bioavailability compared to the pure Gef. Overall, this study suggested that the prepared Gef-SD by microwave method showed marked enhancement in dissolution and bioavailability.

scholarly journals Deprivation of protein or amino acid induces C/EBPβ synthesis and binding to amino acid response elements, but its action is not an absolute requirement for enhanced transcription

2008 ◽  
Vol 410 (3) ◽  
pp. 473-484 ◽  
Author(s):  
Michelle M. Thiaville ◽  
Elizabeth E. Dudenhausen ◽  
Can Zhong ◽  
Yuan-Xiang Pan ◽  
Michael S. Kilberg
Keyword(s):  
Amino Acid ◽  
Dna Binding ◽  
Transcriptional Activation ◽  
Target Genes ◽  
Activating Transcription Factor 3 ◽  
Binding Studies ◽  
Human Hepatoma Cells ◽  
Amino Acid Response

A nutrient stress signalling pathway is triggered in response to protein or amino acid deprivation, namely the AAR (amino acid response), and previous studies have shown that C/EBPβ (CCAAT/enhancer-binding protein β) expression is up-regulated following activation of the AAR. DNA-binding studies, both in vitro and in vivo, have revealed increased C/EBPβ association with AARE (AAR element) sequences in AAR target genes, but its role is still unresolved. The present results show that in HepG2 human hepatoma cells, the total amount of C/EBPβ protein, both the activating [LAP* and LAP (liver-enriched activating protein)] and inhibitory [LIP (liver-enriched inhibitory)] isoforms, was increased in histidine-deprived cells. Immunoblotting of subcellular fractions and immunostaining revealed that most of the C/EBPβ was located in the nucleus. Consistent with these observations, amino acid limitation caused an increase in C/EBPβ DNA-binding activity in nuclear extracts and chromatin immunoprecipitation revealed an increase in C/EBPβ binding to the AARE region in vivo, but at a time when transcription from the target gene was declining. A constant fraction of the basal and increased C/EBPβ protein was phosphorylated on Thr235 and the phospho-C/EBPβ did bind to an AARE. Induction of AARE-enhanced transcription was slightly greater in C/EBPβ-deficient MEFs (mouse embryonic fibroblasts) or C/EBPβ siRNA (small interfering RNA)-treated HepG2 cells compared with the corresponding control cells. Transient expression of LAP*, LAP or LIP in C/EBPβ-deficient fibroblasts caused suppression of increased transcription from an AARE-driven reporter gene. Collectively, the results demonstrate that C/EBPβ is not required for transcriptional activation by the AAR pathway but, when present, acts in concert with ATF3 (activating transcription factor 3) to suppress transcription during the latter stages of the response.

Selenium-Containing Curcumin Polymer for Anti-Liver Fibrosis

2011 ◽  
Vol 311-313 ◽  
pp. 1061-1064
Author(s):  
Yi Feng Zhu ◽  
Jing Neng ◽  
Lei Lei He ◽  
Hua Dong Tang
Keyword(s):  
Molecular Weight ◽  
Polyethylene Glycol ◽  
Amino Acid ◽  
Liver Fibrosis ◽  
Water Soluble ◽  
Sprague Dawley ◽  
Sprague Dawley Rats

A new selenium-containing curcumin polymer was synthesized by polycondensation of curcumin with dihydride, polyethylene glycol, and selenium amino acid monomers. The polymer was stable, water soluble, and injectable with a molecular weight of 6.1x104Da. The in vivo anti-liver fibrosis efficacy of the polymer was investigated with Sprague Dawley rats. The results showed the curcumin polymer had strong anti-hepafibrosis activity.

Removal of Protein-Bound Uremic Toxins by Liposome-Supported Peritoneal Dialysis

2019 ◽  
Vol 39 (6) ◽  
pp. 509-518
Author(s):  
Yuanyuan Shi ◽  
Huajun Tian ◽  
Yifeng Wang ◽  
Yue Shen ◽  
Qiuyu Zhu ◽  
...  
Keyword(s):  
Peritoneal Dialysis ◽  
Uremic Toxins ◽  
Water Soluble ◽  
Sprague Dawley ◽  
Promising Alternative ◽  
Small Water ◽  
Artificial Plasma ◽  
End Stage

Background Protein-bound uremic toxins (PBUTs) are poorly cleared by peritoneal dialysis (PD). This study aimed to enhance PBUT removal in PD by adding a binder to the peritoneal dialysate and to evaluate the feasibility and efficacy of liposome-supported PD (LSPD) to increase the removal of PBUTs compared with albumin PD. Methods Removal of p-cresyl sulfate (PCS), indoxyl sulfate (IS), and indole-3-acetic acid (3-IAA) was first evaluated in an in vitro PD model using artificial plasma preloaded with test solutes. Male Sprague-Dawley rats ( n = 24) were then subjected to 5/6 nephrectomy and fed for 16 weeks to establish end-stage renal failure, after which they were treated with either conventional glucose-based PD, albumin-based PD, or liposome-based PD. Removal of PBUTs and small water-soluble solutes was determined during a 6-hour PD dwell. Results In vitro experiments showed that adding albumin as a toxin binder to the dialysate markedly increased the removal of PCS, IS, and 3-IAA compared with the control. The uptake capacity of liposomes was comparable with that of albumin for PCS and 3-IAA, though slightly inferior for IS. In vivo PD in uremic rats demonstrated that LSPD resulted in higher intraperitoneal concentrations and more total mass removal for PBUTs than the conventional glucose-based PD, which was comparable with albumin PD. Conclusions Supplementing conventional glucose-based PD solutions with a binder could efficiently increase the removal of PBUTs. This preliminary study suggested that LSPD may be a promising alternative to albumin PD for increasing PBUT removal in the development of next-generation PD solutions for PD patients.

scholarly journals Sustained In Vitro and In Vivo Delivery of Metformin from Plant Pollen-Derived Composite Microcapsules

Pharmaceutics ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1048
Author(s):  
Noha M. Meligi ◽  
Amro K.F. Dyab ◽  
Vesselin N. Paunov
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Phoenix Dactylifera ◽  
Relative Bioavailability ◽  
Diabetic Rats ◽  
In Vivo Studies ◽  
Pharmacokinetic Parameters ◽  
Sprague Dawley

We developed a dual microencapsulation platform for the type 2 diabetes drug metformin (MTF), which is aimed to increase its bioavailability. We report the use of Lycopodium clavatum sporopollenin (LCS), derived from their natural spores, and raw Phoenix dactylifera L. (date palm) pollens (DPP) for MTF microencapsulation. MTF was loaded into LCS and DPP via a vacuum and a novel method of hydration-induced swelling. The loading capacity (LC) and encapsulation efficiency (EE) percentages for MTF-loaded LCS and MTF-loaded DPP microcapsules were 14.9% ± 0.7, 29.8 ± 0.8, and 15.2% ± 0.7, 30.3 ± 1.0, respectively. The release of MTF from MTF-loaded LCS microcapsules was additionally controlled by re-encapsulating the loaded microcapsules into calcium alginate (ALG) microbeads via ionotropic gelation, where the release of MTF was found to be significantly slower and pH-dependent. The pharmacokinetic parameters, obtained from the in vivo study, revealed that the relative bioavailability of the MTF-loaded LCS-ALG beads was 1.215 times higher compared to pure MTF, following oral administration of a single dose equivalent to 25 mg/kg body weight MTF to streptozotocin (STZ)-induced diabetic male Sprague-Dawley rats. Significant hypoglycemic effect was obtained for STZ-induced diabetic rats orally treated with MTF-loaded LCS-ALG beads compared to control diabetic rats. Over a period of 29 days, the STZ-induced diabetic rats treated with MTF-loaded LCS-ALG beads showed a decrease in the aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglycerides, cholesterol, and low-density lipoprotein-cholesterol (LDL-C) levels, as well as an increase in glutathione peroxidase (GPx) and a recovery in the oxidative stress biomarker, lipid peroxidation (LPx). In addition, histopathological studies of liver, pancreas, kidney, and testes suggested that MTF-loaded LCS-ALG beads improved the degenerative changes in organs of diabetic rats. The LCS-ALG platform for dual encapsulation of MTF achieved sustained MTF delivery and enhancement of bioavailability, as well as the improved biochemical and histopathological characteristics in in vivo studies, opening many other intriguing applications in sustained drug delivery.

scholarly journals Pharmacokinetics of 1-(2-fluoro-5-methyl-beta-L-arabinofuranosyl)uracil in woodchucks.

1997 ◽  
Vol 41 (10) ◽  
pp. 2184-2187 ◽  
Author(s):  
J W Witcher ◽  
F D Boudinot ◽  
B H Baldwin ◽  
M A Ascenzi ◽  
B C Tennant ◽  
...  
Keyword(s):  
Animal Model ◽  
Oral Administration ◽  
Intravenous Administration ◽  
High Performance ◽  
Hepatitis Virus ◽  
Volume Of Distribution ◽  
Terminal Phase ◽  
Intravenous And Oral Administration

1-(2-Fluoro-5-methyl-beta-L-arabinofuranosyl)uracil (L-FMAU) is a nucleoside analog with potent in vitro activity against hepatitis B virus (HBV) and Epstein-Barr virus. The purpose of this study was to characterize the disposition of L-FMAU following oral and intravenous administration in the woodchuck animal model. The numerous similarities between woodchuck hepatitis virus and HBV infection justify the use of the woodchuck as an animal model for preclinical studies of anti-HBV agents in vivo. Woodchucks were given 25 mg of L-FMAU per kg of body weight intravenously and orally. Concentrations of L-FMAU in urine and plasma were determined by high-performance liquid chromatography. Following intravenous administration of 25 mg of L-FMAU per kg to woodchucks, total clearance was moderate, averaging 0.23 +/- 0.07 liter/h/kg. Renal clearance and nonrenal clearance averaged 0.13 +/- 0.08 and 0.10 +/- 0.06 liter/h/kg, respectively. The steady-state volume of distribution averaged 0.99 +/- 0.17 liter/kg, indicative of intracellular distribution of the nucleoside. The terminal-phase half-life of L-FMAU following intravenous administration averaged 6.2 +/- 2.0 h, and mean residence time averaged 4.5 +/- 0.8 h. Absorption of L-FMAU after oral administration was incomplete, and bioavailability was approximately 20%. Concentrations of L-FMAU in plasma remained above the in vitro 50% effective concentration of 0.026 microg/ml for HBV (C. K. Chu, T. Ma, K. Shanmuganathan, C. Wang, Y. Xiang, S. B. Pai, G.-Q. Yao, J.-P. Sommadossi, and Y.-C. Cheng, Antimicrob. Agents Chemother. 39:979-981, 1995) for 24 h after both intravenous and oral administration of 25 mg of L-FMAU per kg.

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