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 Interpretation of Non-Clinical Data for Prediction of Human Pharmacokinetic Parameters: In Vitro-In Vivo Extrapolation and Allometric Scaling

Pharmaceutics ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 168 ◽  
Author(s):  
Go-Wun Choi ◽  
Yong-Bok Lee ◽  
Hea-Young Cho
Keyword(s):  
Development Process ◽  
Allometric Scaling ◽  
Prediction Method ◽  
Volume Of Distribution ◽  
Pharmacokinetic Parameters ◽  
Elimination Half ◽  
Human Pharmacokinetic ◽  
In Vivo Extrapolation

Extrapolation of pharmacokinetic (PK) parameters from in vitro or in vivo animal to human is one of the main tasks in the drug development process. Translational approaches provide evidence for go or no-go decision-making during drug discovery and the development process, and the prediction of human PKs prior to the first-in-human clinical trials. In vitro-in vivo extrapolation and allometric scaling are the choice of method for projection to human situations. Although these methods are useful tools for the estimation of PK parameters, it is a challenge to apply these methods since underlying biochemical, mathematical, physiological, and background knowledge of PKs are required. In addition, it is difficult to select an appropriate methodology depending on the data available. Therefore, this review covers the principles of PK parameters pertaining to the clearance, volume of distribution, elimination half-life, absorption rate constant, and prediction method from the original idea to recently developed models in order to introduce optimal models for the prediction of PK parameters.

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 Potentials of marine natural products against malaria, leishmaniasis, and trypanosomiasis parasites: a review of recent articles

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Justus Amuche Nweze ◽  
Florence N. Mbaoji ◽  
Yan-Ming Li ◽  
Li-Yan Yang ◽  
Shu-Shi Huang ◽  
...  
Keyword(s):  
Natural Products ◽  
Drug Discovery ◽  
Marine Natural Products ◽  
Neglected Tropical Diseases ◽  
Marine Organisms ◽  
New Drugs ◽  
Screening Methods ◽  
Pharmaceutical Industries

Abstract Background Malaria and neglected communicable protozoa parasitic diseases, such as leishmaniasis, and trypanosomiasis, are among the otherwise called diseases for neglected communities, which are habitual in underprivileged populations in developing tropical and subtropical regions of Africa, Asia, and the Americas. Some of the currently available therapeutic drugs have some limitations such as toxicity and questionable efficacy and long treatment period, which have encouraged resistance. These have prompted many researchers to focus on finding new drugs that are safe, effective, and affordable from marine environments. The aim of this review was to show the diversity, structural scaffolds, in-vitro or in-vivo efficacy, and recent progress made in the discovery/isolation of marine natural products (MNPs) with potent bioactivity against malaria, leishmaniasis, and trypanosomiasis. Main text We searched PubMed and Google scholar using Boolean Operators (AND, OR, and NOT) and the combination of related terms for articles on marine natural products (MNPs) discovery published only in English language from January 2016 to June 2020. Twenty nine articles reported the isolation, identification and antiparasitic activity of the isolated compounds from marine environment. A total of 125 compounds were reported to have been isolated, out of which 45 were newly isolated compounds. These compounds were all isolated from bacteria, a fungus, sponges, algae, a bryozoan, cnidarians and soft corals. In recent years, great progress is being made on anti-malarial drug discovery from marine organisms with the isolation of these potent compounds. Comparably, some of these promising antikinetoplastid MNPs have potency better or similar to conventional drugs and could be developed as both antileishmanial and antitrypanosomal drugs. However, very few of these MNPs have a pharmaceutical destiny due to lack of the following: sustainable production of the bioactive compounds, standard efficient screening methods, knowledge of the mechanism of action, partnerships between researchers and pharmaceutical industries. Conclusions It is crystal clear that marine organisms are a rich source of antiparasitic compounds, such as alkaloids, terpenoids, peptides, polyketides, terpene, coumarins, steroids, fatty acid derivatives, and lactones. The current and future technological innovation in natural products drug discovery will bolster the drug armamentarium for malaria and neglected tropical diseases.

scholarly journals Utilizing in vitro transporter data in IVIVE-PBPK: an overview

ADMET & DMPK ◽  
2017 ◽  
Vol 5 (4) ◽  
pp. 201-211 ◽  
Author(s):  
Pankajini Mallick
Keyword(s):  
Drug Discovery ◽  
Drug Transporters ◽  
Drug Discovery And Development ◽  
Pbpk Models ◽  
Physiologically Based Pharmacokinetic ◽  
Human Pharmacokinetic ◽  
Development Processes ◽  
Key Aspects

In vitro-in vivo extrapolation (IVIVE) integrated in physiologically-based pharmacokinetic (PBPK) models have been increasingly used during drug discovery and development processes to predict human pharmacokinetic (PK) parameters. Drug transporters can influence drug pharmacokinetics and are key aspects contributing to the development of a successful drug. This review provides a snapshot of challenges or shortcomings of in vitro and in vivo techniques for understanding the contribution of drug transporters to a drug’s pharmacokinetics. The paper also describes the potential of IVIVE-PBPK models as prospective approaches to predict the role of drug transporters in drug discovery and development.

scholarly journals Hydroxychloroquine, nitazoxanide and ivermectin have similar effects in early COVID-19: a head-to-head comparison of the Pre-AndroCoV Trial.

2020 ◽  
Author(s):  
Flavio A. Cadegiani ◽  
Andy Goren ◽  
John McCoy ◽  
Carlos Gustavo Wambier
Keyword(s):  
Vitamin C ◽  
Antiviral Activity ◽  
Safety Profile ◽  
New Drugs ◽  
Open Label ◽  
Medical Visits ◽  
Drug Classes ◽  
Potential Efficacy

Abstract Background: COVID-19 pandemic requires urgent responses in terms of identification of effective and safe therapies to reduce hospitalization, death, and post-COVID symptoms, while vaccines are not extensively available. Repurposing already existing medications for COVID-19 should be preferred over the development of new drugs due to their inherent advantages of well-established safety profile, familiarity, and cost. Although antiandrogens have strong plausibility to be effective against COVID-19, hydroxychloroquine, nitazoxanide and ivermectin gained unquestionable popularity due to their in vitro and in vivo direct or indirect antiviral activity, and preliminary observations of efficacy against COVID-19. The objective of the present open-label prospective observational study (the pre-AndroCoV trial) was to make a head-to-head comparative analysis between hydroxychloroquine, nitazoxanide and ivermectin, in terms of potential efficacy for COVID-19, combined with early COVID-19 detection, aiming to choose one of these three drugs to include in the AndroCoV randomized clinical trial (RCT).Materials and methods: Participants were recruited from social media and referred from other medical centers. Patients confirmed for COVID-19 with positive rtPCR-SARS-CoV-2 with fewer than seven days of symptoms and four days of treatment were included. Patients were actively questioned for age, sex, body mass index (BMI), presence of approximately 40 existing diseases and regular use of 30 drug classes, and COVID-19 symptomatology. Hydroxychloroquine 400mg/day for five days, nitazoxanide 500mg twice daily for six days, or ivermectin 0.2mg/kg/day for three consecutive days was given in a quasi-random manner, in association with azithromycin 500mg/day for five days, and optional addition of vitamin C, vitamin D and zinc, and glucocorticoids and anticoagulants in case of signs of lung injury or higher risk for thrombosis, respectively. Patients were followed up for 60 days, including active questions on disease course and symptoms on Days 0, 1, 2, 3, 7, 14 and 30, and virtual medical visits on Days 0 and 14, and whenever symptoms got worse on in the presence of severe adverse effects. Results: In total, 585 participants, including 270 females and 305 males, were included. Of these, 159, 357, and 110 patients received hydroxychloroquine, nitazoxanide, and ivermectin, respectively, with similar baseline characteristics and time-to-treat between them. The three groups had similar duration of positive rtPCR-SARS-CoV-2, clinical disease duration and recovery speed. Of the 585 patients, none was hospitalized, needed mechanical ventilation, or died, and 1.5% persisted with symptoms after recovery.Conclusion: Hydroxychloroquine, nitazoxanide and ivermectin seem to be similarly effective for overall clinical outcomes in COVID-19 when used before seven days of symptoms, and overwhelmingly superior compared to untreated COVID-19 population, even for those outcomes not influenced by placebo effect, at least when combined with azithromycin, and vitamin C, D and zinc in the majority of the cases. Between these drugs, nitazoxanide demonstrated the strongest broad spectrum antiviral activity, plausibility to act as an anti-COVID agent, and safety profile, at least at the time of the choice of the drug for the AndroCoV Trial.

scholarly journals Screening nucleotide and nucleoside analogues as potential inhibitors of SARS-CoV-2 RNA-dependent RNA polymerase by the molecular docking method for the treatment of COVID-19

2021 ◽  
Vol 63 (9) ◽  
pp. 14-21
Author(s):  
Thi Thu Hang Ta ◽  
◽  
Bao Kim Nguyen ◽  
Dang Huy Le ◽  
Thanh Tung Bui ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Rna Polymerase ◽  
Health Concern ◽  
Pharmacokinetic Parameters ◽  
Rna Dependent Rna Polymerase ◽  
Lipinski’S Rule ◽  
Docking Method ◽  
Lipinski’S Rule Of Five

The COVID-19 pandemic triggering acute respiratory syndrome is a major global health concern. The SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) enzyme regulating viral replication has been evaluated as a potential therapeutic target for inhibition of the infection of SARS-CoV-2. In this study, we evaluated the ability of RNA-dependent RNA polymerase drug inhibitors by using molecular docking in silico model. Lipinski’s rule of Five was used to evaluate drug - like properties of potential compound. Pharmacokinetic parameters of potential compounds were assessed using the pkCSM tool. Based on previous publications, we have collected 100 compounds. The results exhibited that 18 compounds have RdRp inhibitory activity stronger than the remdesivir as reference compounds. The Lipinski’s rule of Five showed that 17 among 18 compounds had proprietary drug-likenesss. Compounds including novuridine, didanosine, sofosbuvir, puromycin, defibrotite, gemcitabine, and nikkomycins are the most negative energies and have pharmacokinetic good absorption, not metabolised in the liver, excreted by the kidney and may have hepatotoxicity properties. Therefore, it is necessary to conduct the in vitro and in vivo assays to developthese compounds into drugs for COVID-19 treatment

scholarly journals Docking-Based Screening of Cell-Penetrating Peptides with Antiviral Features and Ebola Virus Proteins as a Drug Discovery Approach to Develop a Treatment for Ebola Virus Disease

2021 ◽  
Author(s):  
Ehsan Raoufi ◽  
Bahar Bahramimeimandi ◽  
Mahsa Darestanifarahani ◽  
Fatemeh Hosseini ◽  
Mohammad Salehi-Shadkami ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Ebola Virus ◽  
Virus Disease ◽  
Cell Penetrating Peptides ◽  
New Drugs ◽  
Cell Penetrating ◽  
Therapeutic Molecules ◽  
Virus Proteins

Ebola drug discovery continues to be challenging as yet. Proteins of the virus should be targeted at the relevant biologically active site for drug or inhibitor binding to be effective. In this regard, by considering the important role of Ebola virus proteins in the viral mechanisms of this viral disease, the Ebola proteins are selected as our drug targets in this study. The discovery of novel therapeutic molecules or peptides will be highly expensive; therefore, we attempted to identify possible antigens of EBOV proteins by conducting docking-based screening of cell penetrating peptides (CPPs) that have antiviral potential features utilizing Hex software version 8.0.0. The E-value scores obtained in this research were very much higher than the previously reported docking studies. CPPs that possess suitable interaction with the targets would be specified as promising candidates for further in vitro and in vivo examination aimed at developing new drugs for Ebola infection treatment.

scholarly journals Metabolic stability and its role in the discovery of new chemical entities

2019 ◽  
Vol 69 (3) ◽  
pp. 345-361 ◽  
Author(s):  
Karolina Słoczyńska ◽  
Agnieszka Gunia-Krzyżak ◽  
Paulina Koczurkiewicz ◽  
Katarzyna Wójcik-Pszczoła ◽  
Dorota Żelaszczyk ◽  
...  
Keyword(s):  
Parent Compound ◽  
Metabolic Stability ◽  
Pharmacokinetic Parameters ◽  
Toxic Metabolites ◽  
New Chemical Entities ◽  
Preclinical Species ◽  
Therapeutic Compounds

Abstract Determination of metabolic profiles of new chemical entities is a key step in the process of drug discovery, since it influences pharmacokinetic characteristics of therapeutic compounds. One of the main challenges of medicinal chemistry is not only to design compounds demonstrating beneficial activity, but also molecules exhibiting favourable pharmacokinetic parameters. Chemical compounds can be divided into those which are metabolized relatively fast and those which undergo slow biotransformation. Rapid biotransformation reduces exposure to the maternal compound and may lead to the generation of active, non-active or toxic metabolites. In contrast, high metabolic stability may promote interactions between drugs and lead to parent compound toxicity. In the present paper, issues of compound metabolic stability will be discussed, with special emphasis on its significance, in vitro metabolic stability testing, dilemmas regarding in vitro-in vivo extrapolation of the results and some aspects relating to different preclinical species used in in vitro metabolic stability assessment of compounds.

scholarly journals In vitro Metabolic Stability of Drugs and Applications of LC-MS in Metabolite Profiling

2021 ◽  
Author(s):  
Marothu Vamsi Krishna ◽  
Kantamaneni Padmalatha ◽  
Gorrepati Madhavi
Keyword(s):  
Drug Discovery ◽  
Metabolite Profiling ◽  
Neutral Loss ◽  
The Body ◽  
Metabolic Stability ◽  
Mass Defect ◽  
Identification Process ◽  
Isotope Pattern

Metabolic stability of a compound is an important factor to be considered during the early stages of drug discovery. If the compound has poor metabolic stability, it never becomes a drug even though it has promising pharmacological characteristics. For example, a drug is quickly metabolized in the body; it does not have sufficient in vivo exposure levels and leads to the production of toxic, non-active or active metabolites. A drug is slowly metabolized in the body it could remain longer periods in the body and lead to unwanted adverse reactions, toxicity or may cause drug interactions. Metabolic stability assay is performed to understand the susceptibility of the compound to undergo biotransformation in the body. Intrinsic clearance of the compound is measured by metabolic stability assays. Different in vitro test systems including liver microsomes, hepatocytes, S9 fractions, cytosol, recombinant expressed enzymes, and cell lines are used to investigate the metabolic stability of drugs. Metabolite profiling is a vital part of the drug discovery process and LC–MS plays a vital role. The development of high-resolution (HR) MS technologies with improved mass accuracy, in conjunction with novel data processing techniques, has significantly improved the metabolite detection and identification process. HR-MS based data acquisition (ion intensity-dependent acquisition, accurate-mass inclusion list-dependent acquisition, isotope pattern-dependent acquisition, pseudo neutral loss-dependent acquisition, and mass defect-dependent acquisition) and data mining techniques (extracted ion chromatogram, product ion filter, mass defect filter, isotope pattern filter, neutral loss filter, background subtraction, and control sample comparison) facilitate the drug metabolite identification process.

Sign in / Sign up

Export Citation Format

Share Document