Absorption, metabolism, and excretion of 14C gimatecan (LBQ707) after oral administration in patients with advanced cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2564-2564 ◽  
Author(s):  
M. M. Woo ◽  
L. Rodriguez ◽  
H. Gu ◽  
K. Crenshaw-Williams ◽  
F. Rocha ◽  
...  
Keyword(s):  
Advanced Cancer ◽  
Topoisomerase I ◽  
Oral Absorption ◽  
Total Radioactivity ◽  
Fecal Excretion ◽  
Active Components ◽  
Good Tolerability ◽  
Radiometric Detection ◽  
Pharmacologically Active

2564 Background: Gimatecan (Gim), a new potent oral topoisomerase I inhibitor is a lipophilic 7-oxyiminomethyl derivative of camptothecin. Its in vitro cytoxicity is more sustained than CPT-11 and topotecan, it has excellent anti-tumor activity in mouse xenografts, and shown good tolerability with Ph I activity. The study aim was to profile its disposition in cancer patients. Methods: 4 patients with advanced cancer received a single oral 1.5 mg dose of [14C] Gim (60 μCi) followed by standard Gim treatment on Day 15. Whole blood, plasma, urine, and feces were collected over 7 days with spot fecal collections up to Day 19. Total radioactivity was measured by liquid scintillation counting. Gim and metabolite concentrations in plasma and excreta were measured by LC- MS/MS and HPLC with radiometric detection. Results: Gim showed a rapid first-order absorption and a long elimination phase and was well tolerated. The median (range) Tmax for Gim was 1 h (0.5 to 3 h) and mean t1/2 and oral clearance values were 91 h and 0.6 L/h, respectively. Gim was the major moiety and its active metabolite LCF775 (t-butyl-mono-hydroxy Gim) was the main metabolite (albeit minor, 2–9%) in plasma. Trace glucuronide and sulfate metabolites were also detected in plasma. Mean recovery of radioactivity in urine (0-Day 7) and feces (0-Day 11) was 70.5 % (56.2–80.0%) of the dose. Incomplete recovery is attributed to opiates use in 2 patients and incomplete (sporadic) fecal sampling at later timepoints. Fecal excretion (0-Day 11) was prolonged and major in 3/4 patients (46- 73% of the dose, of which 14–23% is the unchanged Gim suggesting the drug is well absorbed). An additional 1.3–3.5% was recovered in spot collections (Days 14, 15 and 19). Urine excretion (0-Day 7) was 7.2–10.3% of the dose in 3 patients, one patient (cachectic, on opiates) excreted only 21% in feces and 46% in urine. Gim and several Gim metabolites (and glucuronide conjugates thereof) were the major components in excreta. Conclusions: Gim and its minor metabolite, LCF775 were the principal pharmacologically active components in plasma. Fecal excretion is the main elimination pathway in most patients. A long half-life (90hr) of Gim, uncomplicated metabolism, and good oral absorption make Gim an attractive candidate for Ph II development. [Table: see text]

Elucidation of the metabolic and elimination pathways of panobinostat (LBH589) using [14C]-panobinostat

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2549-2549 ◽  
Author(s):  
S. Clive ◽  
M. M. Woo ◽  
M. Stewart ◽  
T. Nydam ◽  
S. Hirawat ◽  
...  
Keyword(s):  
Blood Plasma ◽  
Hydroxamic Acid ◽  
Oral Absorption ◽  
Total Radioactivity ◽  
Side Chain ◽  
Clinical Activity ◽  
Deacetylase Inhibitor ◽  
Radiometric Detection ◽  
Major Route ◽  
Clinically Significant

2549 Background: Panobinostat (PAN), a hydroxamic acid derivative, is a potent pan-deacetylase inhibitor, demonstrating anti-tumor activities in a wide variety of preclinical models and showing promising clinical activity. This study elucidates the metabolic and elimination pathways of PAN using [14C]-PAN. Methods: Four patients with advanced cancer received a single oral 20 mg dose of [14C]-PAN (50 μCi). Whole blood, plasma, urine, and feces were collected over 7 days. Total radioactivity was measured in blood, plasma, and excreta by liquid scintillation counting. PAN and its metabolite concentrations in plasma and excreta were measured by LC-MS/MS and HPLC with radiometric detection. Patients were monitored for safety. Results: The single PAN dose was well tolerated with no clinically significant laboratory or ECG abnormalities observed. PAN had a rapid oral absorption [median Tmax 0.8 h (range, 0.5–1 h)] and moderate elimination (median t1/2 31 h). The median t1/2 for blood and plasma radioactivity was 54 and 75 hours, respectively. Mass balance was achieved with ≥87% of the administered radioactivity being recovered in the excreta of all patients after 7 days. 44–77% and 29–51% of the dose was recovered in the feces and urine, respectively. Unchanged PAN accounted for ≤3% of the administered dose in the feces, suggesting good oral absorption. The most prominent metabolic pathways involved modifications of the hydroxamic acid (HA) side chain, to form an amide via reduction, carboxylic acid via either hydrolysis or one- and two-carbon (M1) shortening of the HA side chain. Oxygenation and glucuronidation were also observed. PAN accounted for ≤9% of the total radioactivity AUC. The most abundant circulating metabolites in plasma were the glucuronide of M1 (19%) and carbamoyl glucuronide of PAN (13%). At least 40 metabolites, many at trace levels, were observed circulating in plasma. Conclusions: PAN and its metabolites are equally excreted in the urine and feces. Elimination of PAN is primarily by metabolism via reduction, hydrolysis, oxidation and glucuronidation. The balanced elimination and absence of a single major route of PAN metabolism suggest that clinical drug-drug interactions are unlikely with PAN. [Table: see text]

scholarly journals Quantitative standardization of pharmacologically active components from antiplasmodial plant Solanum nudum Dunal (wild and in vitro)

2022 ◽  
Vol 21 (1) ◽  
pp. 41-50
Author(s):  
Ana Maria Mesa-Vanegas ◽  
◽  
Esther Julia Naranjo-Gomez ◽  
Felipe Cardona ◽  
Lucia Atehortua-Garces ◽  
...  
Keyword(s):  
Pacific Coast ◽  
Inhibitory Concentration ◽  
Quality Parameter ◽  
Antimalarial Treatment ◽  
Active Components ◽  
Steroidal Compound ◽  
Pharmacologically Active ◽  
Article Study ◽  
Over Time

Solanum nudum Dunal (Solanaceae) is most commonly known and used by the population of the colombian Pacific coast as an antimalarial treatment. This article study into optimization and quantitative analysis of compounds steroidal over time of development of this species when grown in vitro and wild. A new steroidal compound named SN6 was elucidated by NMR and a new method of quantification of seven steroidal compounds (Diosgenone DONA and six steroids SNs) using HPLC-DAD-MS in extracts of cultures in vitro and wild was investigated. Biology activity of extracts was found to a range of antiplasmodial activity in FCB2 and NF-54 with inhibitory concentration (IC50) between (17.04 -100 μg/mL) and cytotoxicity in U-937 of CC50 (7.18 -104.7 μg/mL). This method creates the basis for the detection of seven sterols antiplasmodial present in extracts from S. nudum plant as a quality parameter in the control and expression of phytochemicals.

scholarly journals APPLICATION OF ELICITOR FOR PRODUCTION OF SAPONINS FROM IN VITRO PANAX CULTURES

2018 ◽  
Vol 16 (2) ◽  
pp. 211-221
Author(s):  
Nguyen Thi Nhat Linh ◽  
Nguyen Hoang Loc ◽  
Duong Tan Nhut
Keyword(s):  
Metabolic Engineering ◽  
Large Scale ◽  
Optimal Solution ◽  
Scale Production ◽  
Triterpene Saponins ◽  
Active Components ◽  
Triterpene Saponin ◽  
Saponin Content ◽  
Pharmacologically Active

The Panax ginseng species are traditional medicinal herbs having high value. The major pharmacologically active components are the ginsenosides of saponin group, which are dammarane type triterpene glycosides containing a tetracyclic glycose. Ginseng saponin, one of the secondary metabolites, is necessary for the growth and development of Panax genus plants. In pharmaceutical industry, triterpene saponins were purified to produce drugs for its promising healing and restorative properties. However, commercial applications are still obstacle for practical problems, because ginseng natural resources are rarely precious; and ginseng resources from field have low and variable yields dependent on season or quality of soil. Moreover, triterpene saponins have complex structures, making chemical synthesis an economically uncompetitive option for large-scale production. A current alternative optimal solution that is popular in the world is the application of cell and tissue culture to produce a large of cell or root yield in short time. But the difficulty in producing triterpene saponins from in vitro culture is that the triterpene saponin content is much lower than natural. To increase the triterpene saponin content, elicitors are added to the culture medium. Based on the effect of the elicitor, metabolic engineering in vitro is also able to enhance the overexpression of genes which translated enzymes or signals producing saponin in the isoprenoid pathway. Application of elicitor researches could improve triterpene saponin yields or adjust specific desired triterpene saponins from in vitro ginseng culture. Therefore, we review the recent studies of elicitor in Panax genus cultures and saponin biosynthetic gene to study and assess the efficiency of elicitors in triterpene saponin production and metabolic engineering of triterpene saponins.

scholarly journals Single-Dose Pharmacokinetics and Metabolism of [14C]Remofovir in Rats and Cynomolgus Monkeys

2005 ◽  
Vol 49 (3) ◽  
pp. 925-930 ◽  
Author(s):  
Chin-Chung Lin ◽  
Christine Xu ◽  
Nanqun Zhu ◽  
David Lourenco ◽  
Li-Tain Yeh
Keyword(s):  
Single Dose ◽  
Oral Dose ◽  
Oral Administration ◽  
Oral Absorption ◽  
Urinary Metabolites ◽  
Apparent Volume ◽  
Volume Of Distribution ◽  
Total Radioactivity ◽  
Fecal Excretion ◽  
Total Body

ABSTRACT Single-dose pharmacokinetics and metabolism of [14C]remofovir was studied in rats and monkeys following intravenous (i.v.) and oral administration (30 mg/kg of body weight). Oral absorption and bioavailability were 29.7 and 5.42% in rats and 65.6 and 19.4% in monkeys, respectively. Following i.v. administration, the elimination half-life for remofovir was 0.7 h in both rats and monkeys. Total body clearance was 5.85 liters/h/kg in rats and 2.60 liters/h/kg in monkeys; apparent volume of distribution was 5.99 liters/kg in rats and 2.70 liters/kg in monkeys. Following oral administration, remofovir was extensively converted to 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and other metabolites in both species. In rats, excretion of total radioactivity in urine accounted for 61.8% of the i.v. dose and 12.9% of the oral dose, while in monkeys it accounted for 43.3% of the i.v. dose and 34.9% of the oral dose. Following i.v. dosing of [14C]remofovir, fecal excretion of radioactivity accounted for 37.5% of the dose in rats and 17.4% of the dose in monkeys, indicating significant biliary excretion of the drug in animals. PMEA and metabolite A were the major urinary metabolites in both species after i.v. and oral administration of remofovir.

Formulation and Evaluation of Solubility Enhanced Ciprofloxacin

2013 ◽  
Vol 6 (3) ◽  
pp. 2131-2136
Author(s):  
R S Thakur ◽  
A Nayaz ◽  
Y Koushik
Keyword(s):  
Oral Absorption ◽  
Polymeric Micelles ◽  
In Vitro Release ◽  
Microemulsion System ◽  
Salt Form ◽  
Solubility Study ◽  
Ternary Phase Diagrams ◽  
Blood Ph ◽  
Vitro Release

In the case of solubility limited absorption, creating supersaturation in the GI fluid is very critical as supersaturation may provide great improvement of oral absorption. The techniques to create the so-called supersaturation in the GI fluid include microemulsions, emulsions, liposomes, complexations, polymeric micelles, and conventional micelles. Ciprofloxacin was chosen because it is practically insoluble in water; hence its salt form is used commercially, which is soluble in water. The objective of the present investigation was to enhance the solubility of Ciprofloxacin by formulating it into microemulsion system. For this purpose, initially, surfactant and cosurfactant were selected based on their HLB value, followed by pseudo-ternary phase diagrams to identify the microemulsion existing zone. Different formulations were developed and evaluated for pH, conductivity, in vitro release and stability. Solubility study was performed for optimized formulation. The pH of the designed formulations varied from 6.02-7.04. This was ideal and near blood pH 7.4. Conductivity data indicated that the microemulsion was of the o/w type. In vitro release of optimized formulation(FM3) was 95.2% as compared to pure drug 46.61% after 90 min and marketed product(salt form) 93.9%. Hence, by formulating into microemulsion, the solubility of ciprofloxacin is significantly enhanced.    

In Silico Appraisal, Synthesis, Antibacterial Screening and DNA Cleavage for 1,2,5-thiadiazole Derivative

2019 ◽  
Vol 15 (5) ◽  
pp. 445-455 ◽  
Author(s):  
Suraj N. Mali ◽  
Sudhir Sawant ◽  
Hemchandra K. Chaudhari ◽  
Mustapha C. Mandewale
Keyword(s):  
Molecular Docking ◽  
Dna Cleavage ◽  
In Silico ◽  
Oral Absorption ◽  
Inhibition Mechanism ◽  
Hydrogen Binding ◽  
Docking Score ◽  
Antibacterial Screening ◽  
Mycobacteria Tuberculosis

Background: : Thiadiazole not only acts as “hydrogen binding domain” and “two-electron donor system” but also as constrained pharmacophore. Methods:: The maleate salt of 2-((2-hydroxy-3-((4-morpholino-1, 2,5-thiadiazol-3-yl) oxy) propyl) amino)- 2-methylpropan-1-ol (TML-Hydroxy)(4) has been synthesized. This methodology involves preparation of 4-morpholino-1, 2,5-thiadiazol-3-ol by hydroxylation of 4-(4-chloro-1, 2,5-thiadiazol-3-yl) morpholine followed by condensation with 2-(chloromethyl) oxirane to afford 4-(4-(oxiran-2-ylmethoxy)-1,2,5-thiadiazol- 3-yl) morpholine. Oxirane ring of this compound was opened by treating with 2-amino-2-methyl propan-1- ol to afford the target compound TML-Hydroxy. Structures of the synthesized compounds have been elucidated by NMR, MASS, FTIR spectroscopy. Results: : The DSC study clearly showed that the compound 4-maleate salt is crystalline in nature. In vitro antibacterial inhibition and little potential for DNA cleavage of the compound 4 were explored. We extended our study to explore the inhibition mechanism by conducting molecular docking, ADMET and molecular dynamics analysis by using Schrödinger. The molecular docking for compound 4 showed better interactions with target 3IVX with docking score of -8.508 kcal/mol with respect to standard ciprofloxacin (docking score= -3.879 kcal/mol). TML-Hydroxy was obtained in silico as non-carcinogenic and non-AMES toxic with good percent human oral absorption profile (69.639%). TML-Hydroxy showed the moderate inhibition against Mycobacteria tuberculosis with MIC 25.00 μg/mL as well as moderate inhibition against S. aureus, Bacillus sps, K. Pneumoniae and E. coli species. Conclusion: : In view of the importance of the 1,2,5-thiadiazole moiety involved, this study would pave the way for future development of more effective analogs for applications in medicinal field.

Formulation and Characterization of Glimepiride Nanoparticles for Dissolution Enhancement

2020 ◽  
Vol 10 (5) ◽  
pp. 649-663
Author(s):  
Reena Siwach ◽  
Parijat Pandey ◽  
Harish Dureja
Keyword(s):  
Drug Release ◽  
Dissolution Rate ◽  
Oral Absorption ◽  
In Vitro Release ◽  
Entrapment Efficiency ◽  
Class Ii ◽  
Dissolution Enhancement ◽  
In Vitro Drug Release ◽  
Bcs Class Ii

Background: The rate-limiting step in the oral absorption of BCS class II drugs is dissolution. Their low solubility is one of the major obstacles in the process of drug development. Dissolution rate can be increased by decreasing the particle size to the nano range, eventually leading to increased bioavailability. Objective: : In the present study, glimepiride loaded nanoparticles were prepared to enhance the dissolution rate. The aim of the work was to examine the effect of polymer-drug ratio, solvent-antisolvent ratio and speed of mixing on in vitro release of glimepiride. Methods: Glimepiride is an antidiabetic drug belonging to the BCS class II drugs. The polymeric nanoparticles were formulated according to Box-Behnken Design (BBD) using nanoprecipitation technique. The prepared nanoparticles were evaluated for in vitro drug release, loading capacity, entrapment efficiency, and percentage yield. Result: It was found that NP-8 has maximum in vitro drug release and was selected as an optimized batch. Analysis of Variance (ANOVA) was applied to the in vitro drug release to study the fitness and significance of the model. The batch NP-8 showed 70.34 ± 1.09% in vitro drug release in 0.1 N methanolic HCl and 92.02 ± 1.87% drug release in phosphate buffer pH 7.8. The release data revealed that the nanoparticles followed zero order kinetics. Conclusion: The study revealed that the incorporation of glimepiride into gelucire 50/13 resulted in enhanced dissolution rate.

Metal-organic Nanopharmaceuticals

2020 ◽  
Vol 8 (3) ◽  
pp. 163-190
Author(s):  
Benjamin Steinborn ◽  
Ulrich Lächelt
Keyword(s):  
Metal Ions ◽  
Coordination Polymers ◽  
Active Agent ◽  
Lewis Base ◽  
High Loading ◽  
Active Components ◽  
Base Functions ◽  
Metal Organic ◽  
Theranostic Applications ◽  
Pharmacologically Active

: Coordinative interactions between multivalent metal ions and drug derivatives with Lewis base functions give rise to nanoscale coordination polymers (NCPs) as delivery systems. As the pharmacologically active agent constitutes a main building block of the nanomaterial, the resulting drug loadings are typically very high. By additionally selecting metal ions with favorable pharmacological or physicochemical properties, the obtained NCPs are predominantly composed of active components which serve individual purposes, such as pharmacotherapy, photosensitization, multimodal imaging, chemodynamic therapy or radiosensitization. By this approach, the assembly of drug molecules into NCPs modulates pharmacokinetics, combines pharmacological drug action with specific characteristics of metal components and provides a strategy to generate tailorable multifunctional nanoparticles. This article reviews different applications and recent examples of such highly functional nanopharmaceuticals with a high ‘material economy’. : Lay Summary: Nanoparticles, that are small enough to circulate in the bloodstream and can carry cargo molecules, such as drugs, imaging or contrast agents, are attractive materials for pharmaceutical applications. A high loading capacity is a generally aspired parameter of nanopharmaceuticals to minimize patient exposure to unnecessary nanomaterial. Pharmaceutical agents containing Lewis base functions in their molecular structure can directly be assembled into metal-organic nanopharmaceuticals by coordinative interaction with metal ions. Such coordination polymers generally feature extraordinarily high loading capacities and the flexibility to encapsulate different agents for a simultaneous delivery in combination therapy or ‘theranostic’ applications.

scholarly journals A molecularly defined skin test reagent for the diagnosis of bovine tuberculosis compatible with vaccination against Johne’s Disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sonya Middleton ◽  
Sabine Steinbach ◽  
Michael Coad ◽  
Kevina McGill ◽  
Colm Brady ◽  
...  
Keyword(s):  
Skin Test ◽  
Recombinant Proteins ◽  
Bovine Tuberculosis ◽  
Synthetic Peptides ◽  
Blood Test ◽  
High Specificity ◽  
Active Components ◽  
Interferon Gamma Release Assays ◽  
Skin Responses

AbstractTuberculin Purified Protein Derivatives (PPDs) exhibit multiple limitations: they are crude extracts from mycobacterial cultures with largely unknown active components; their production depends on culture of mycobacteria requiring expensive BCL3 production facilities; and their potency depends on the technically demanding guinea pig assay. To overcome these limitations, we developed a molecularly defined tuberculin (MDT) by adding further antigens to our prototype reagent composed of ESAT-6, CFP-10 and Rv3615c (DIVA skin test, DST). In vitro screening using PBMC from infected and uninfected cattle shortlisted four antigens from a literature-based list of 18 to formulate the MDT. These four antigens plus the previously identified Rv3020c protein, produced as recombinant proteins or overlapping synthetic peptides, were formulated together with the three DST antigens into the MDT to test cattle experimentally and naturally infected with M. bovis, uninfected cattle and MAP vaccinated calves. We demonstrated significant increases in MDT-induced skin responses compared to DST in infected animals, whilst maintaining high specificity in unvaccinated or MAP vaccinated calves. Further, MDT can also be applied in in vitro blood-based interferon-gamma release assays. Thus, MDT promises to be a robust diagnostic skin and blood test reagent overcoming some of the limitations of PPDs and warrants full validation.

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