Scaling In Vivo Pharmacokinetics from In Vitro Metabolic Stability Data in Drug Discovery

Eight triazolopyrimidine sulfonanilides were tested for metabolic stability in a number of crop and weed species. These data, along with in vitro determinations of activity (I50) against acetolactate synthase, successfully described the in vivo activity of these compounds in a two-parameter model. Whole plant activity increased with increasing compound stability and decreasing I50 (r2 =.78, N = 36). The difficulty in obtaining metabolic stability data during a structure optimization program prompted a study with substituent parameters in models of in vivo activity. Models describing whole plant activity in jimsonweed were developed using a series of 5-methyl triazolopyrimidine sulfonanilides that differed only in ortho and meta substituents on the aniline ring. The I50 term and clogP were most important to jimsonweed activity. Hence, in vitro activity (I50) may be a useful component of whole plant structure activity models to aid in identification of barriers to in vivo performance.

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

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dku457 ◽

2014 ◽

Vol 70 (3) ◽

pp. 857-867 ◽

Cited By ~ 75

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.

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

10.5772/intechopen.99762 ◽

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.

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Current Approaches to Drug Discovery for Chagas Disease: Methodological Advances

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207322666191010144111 ◽

2019 ◽

Vol 22 (8) ◽

pp. 509-520

Author(s):

Cauê B. Scarim ◽

Chung M. Chin

Keyword(s):

Drug Discovery ◽

Chagas Disease ◽

Drug Candidates ◽

Lead Compounds ◽

New Drug ◽

Compound Libraries ◽

Screening Assays ◽

Cruzi Infection

Background: In recent years, there has been an improvement in the in vitro and in vivo methodology for the screening of anti-chagasic compounds. Millions of compounds can now have their activity evaluated (in large compound libraries) by means of high throughput in vitro screening assays. Objective: Current approaches to drug discovery for Chagas disease. Method: This review article examines the contribution of these methodological advances in medicinal chemistry in the last four years, focusing on Trypanosoma cruzi infection, obtained from the PubMed, Web of Science, and Scopus databases. Results: Here, we have shown that the promise is increasing each year for more lead compounds for the development of a new drug against Chagas disease. Conclusion: There is increased optimism among those working with the objective to find new drug candidates for optimal treatments against Chagas disease.

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In vitro AMPK activating effect and in vivo pharmacokinetics of mogroside V, a cucurbitane-type triterpenoid from Siraitia grosvenorii fruits

RSC Advances ◽

10.1039/c5ra23275a ◽

2016 ◽

Vol 6 (9) ◽

pp. 7034-7041 ◽

Cited By ~ 13

Author(s):

Zuliang Luo ◽

Feng Qiu ◽

Kailun Zhang ◽

Xijun Qin ◽

Yuhua Guo ◽

...

Keyword(s):

Siraitia Grosvenorii ◽

In Vivo Pharmacokinetics

The aim of this study was to explore the anti-diabetic effects of mogroside V (MV) and its aglycone mogrol (MO), both isolated from the fruits of Siraitia grosvenorii Swingle, and to investigate the pharmacokinetic behaviors of MV and its metabolite MO in rats.

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Human Adipose-Derived Stromal/Stem Cell Culture and Analysis Methods for Adipose Tissue Modeling In Vitro: A Systematic Review

Cells ◽

10.3390/cells10061378 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1378

Author(s):

Peyton Gibler ◽

Jeffrey Gimble ◽

Katie Hamel ◽

Emma Rogers ◽

Michael Henderson ◽

...

Keyword(s):

Systematic Review ◽

Adipose Tissue ◽

Drug Discovery ◽

3D Culture ◽

Human Adipose Tissue ◽

Culture Methods ◽

Adipose Tissue Engineering ◽

The Impact

Human adipose-derived stromal/stem cells (hASC) are widely used for in vitro modeling of physiologically relevant human adipose tissue. These models are useful for the development of tissue constructs for soft tissue regeneration and 3-dimensional (3D) microphysiological systems (MPS) for drug discovery. In this systematic review, we report on the current state of hASC culture and assessment methods for adipose tissue engineering using 3D MPS. Our search efforts resulted in the identification of 184 independent records, of which 27 were determined to be most relevant to the goals of the present review. Our results demonstrate a lack of consensus on methods for hASC culture and assessment for the production of physiologically relevant in vitro models of human adipose tissue. Few studies have assessed the impact of different 3D culture conditions on hASC adipogenesis. Additionally, there has been a limited use of assays for characterizing the functionality of adipose tissue in vitro. Results from this study suggest the need for more standardized culture methods and further analysis on in vitro tissue functionality. These will be necessary to validate the utility of 3D MPS as an in vitro model to reduce, refine, and replace in vivo experiments in the drug discovery regulatory process.

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Differentiation of human induced pluripotent stem cells into functional airway epithelium

10.1101/2020.11.29.400358 ◽

2020 ◽

Author(s):

Engi Ahmed ◽

Mathieu Fieldes ◽

Chloé Bourguignon ◽

Joffrey Mianné ◽

Aurélie Petit ◽

...

Keyword(s):

Stem Cells ◽

Drug Discovery ◽

Induced Pluripotent Stem Cells ◽

Blood Sample ◽

Pluripotent Stem Cells ◽

Bronchial Epithelium ◽

Neuroendocrine Cells ◽

Induced Pluripotent

AbstractRationaleHighly reproducible in vitro generation of human bronchial epithelium from pluripotent stem cells is an unmet key goal for drug screening to treat lung diseases. The possibility of using induced pluripotent stem cells (hiPSC) to model normal and diseased tissue in vitro from a simple blood sample will reshape drug discovery for chronic lung, monogenic and infectious diseases.MethodsWe devised a simple and reliable method that drives a blood sample reprogrammed into hiPSC subsequently differentiated within 45 days into air-liquid interface bronchial epithelium (iALI), through key developmental stages, definitive-endoderm (DE) and Ventralized-Anterior-Foregut-Endoderm (vAFE) cells.ResultsReprogramming blood cells from one healthy and 3 COPD patients, and from skin-derived fibroblasts obtained in one PCD patient, succeeded in 100% of samples using Sendai viruses. Mean cell purity at DE and vAFE stages was greater than 80%, assessed by expression of CXCR4 and NKX2.1, avoiding the need of cell sorting. When transferred to ALI conditions, vAFE cells reliably differentiated within 4 weeks into bronchial epithelium with large zones covered by beating ciliated, basal, goblets, club cells and neuroendocrine cells as found in vivo. Benchmarking all culture conditions including hiPSCs adaptation to single-cell passaging, cell density and differentiation induction timing allowed for consistently producing iALI bronchial epithelium from the five hiPSC lines.ConclusionsReliable reprogramming and differentiation of blood-derived hiPSCs into mature and functional iALI bronchial epithelium is ready for wider use and this will allow better understanding lung disease pathogenesis and accelerating the development of novel gene therapies and drug discovery.

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