Role of in Vitro Two-dimensional (2D) and Three-dimensional (3D) Cell Culture Systems for ADME-Tox Screening in Drug Discovery and Development: a Comprehensive Review

Overview

Journal ADMET DMPK

Specialty Pharmacology

Date 2023 Feb 13

PMID 36778905

Authors

Venkatesh Chunduri

Srinivas Maddi

Affiliations

Soon will be listed here.

Abstract

Drug discovery and development have become a very time-consuming and expensive process. Preclinical animal models have become the gold standard for studying drug pharmacokinetic and toxicity parameters. However, the involvement of a huge number of animal subjects and inter-species pathophysiological variations between animals and humans has provoked a lot of debate, particularly because of ethical concerns. Although many efforts are being established by biotech and pharmaceutical companies for screening new chemical entities before preclinical trials, failures during clinical trials are still involved. Currently, a large number of two- dimensional (2D) in vitro assays have been developed and are being developed by researchers for the screening of compounds. Although these assays are helpful in screening a huge library of compounds and have shown perception, there is a significant lack in predicting human Absorption, Distribution, Metabolism, Excretion and Toxicology (ADME-Tox). As a result, these assays cannot completely replace animal models. The recent inventions in three-dimensional (3D) cell culture-based assays like organoids and micro-physiological systems have shown great potential alternative tools for predicting the compound pharmacokinetic and pharmacodynamic fate in humans. In this comprehensive review, we have summarized some of the most commonly used 2D in vitro assays and emphasized the achievements in next-generation 3D cell culture-based systems for predicting the compound ADME-Tox.

Citing Articles

An engineered in vitro model of the human myotendinous junction.

Josvai M, Polyak E, Kalluri M, Robertson S, Crone W, Suzuki M Acta Biomater. 2024; 180:279-294.

PMID: 38604466 PMC: 11088524. DOI: 10.1016/j.actbio.2024.04.007.

A phenotypic screening approach to target p60AmotL2-expressing invasive cancer cells.

Fonseca P, Cui W, Struyf N, Tong L, Chaurasiya A, Casagrande F J Exp Clin Cancer Res. 2024; 43(1):107.

PMID: 38594748 PMC: 11003180. DOI: 10.1186/s13046-024-03031-w.

Advantages of Using 3D Spheroid Culture Systems in Toxicological and Pharmacological Assessment for Osteogenesis Research.

Yun C, Kim S, Kim K, Yang M, Byun M, Kim J Int J Mol Sci. 2024; 25(5).

PMID: 38473760 PMC: 10931738. DOI: 10.3390/ijms25052512.

Insights on Three Dimensional Organoid Studies for Stem Cell Therapy in Regenerative Medicine.

Mulaudzi P, Abrahamse H, Crous A Stem Cell Rev Rep. 2023; 20(2):509-523.

PMID: 38095787 PMC: 10837234. DOI: 10.1007/s12015-023-10655-6.

References

Ashburn T, Thor K . Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov. 2004; 3(8):673-83. DOI: 10.1038/nrd1468. View

Herath M, Hosie S, Bornstein J, Franks A, Hill-Yardin E . The Role of the Gastrointestinal Mucus System in Intestinal Homeostasis: Implications for Neurological Disorders. Front Cell Infect Microbiol. 2020; 10:248. PMC: 7270209. DOI: 10.3389/fcimb.2020.00248. View

Alqahtani S, Mohamed L, Kaddoumi A . Experimental models for predicting drug absorption and metabolism. Expert Opin Drug Metab Toxicol. 2013; 9(10):1241-54. DOI: 10.1517/17425255.2013.802772. View

Poisson J, Lemoinne S, Boulanger C, Durand F, Moreau R, Valla D . Liver sinusoidal endothelial cells: Physiology and role in liver diseases. J Hepatol. 2016; 66(1):212-227. DOI: 10.1016/j.jhep.2016.07.009. View

Pocock K, Delon L, Bala V, Rao S, Priest C, Prestidge C . Intestine-on-a-Chip Microfluidic Model for Efficient in Vitro Screening of Oral Chemotherapeutic Uptake. ACS Biomater Sci Eng. 2021; 3(6):951-959. DOI: 10.1021/acsbiomaterials.7b00023. View

Maubon N, Le Vee M, Fossati L, Audry M, Le Ferrec E, Bolze S . Analysis of drug transporter expression in human intestinal Caco-2 cells by real-time PCR. Fundam Clin Pharmacol. 2007; 21(6):659-63. DOI: 10.1111/j.1472-8206.2007.00550.x. View

Berry M, Grivell A, Grivell M, Phillips J . Isolated hepatocytes--past, present and future. Cell Biol Toxicol. 1997; 13(4-5):223-33. DOI: 10.1023/a:1007402505482. View

Kiela P, Ghishan F . Physiology of Intestinal Absorption and Secretion. Best Pract Res Clin Gastroenterol. 2016; 30(2):145-59. PMC: 4956471. DOI: 10.1016/j.bpg.2016.02.007. View

Bavli D, Prill S, Ezra E, Levy G, Cohen M, Vinken M . Real-time monitoring of metabolic function in liver-on-chip microdevices tracks the dynamics of mitochondrial dysfunction. Proc Natl Acad Sci U S A. 2016; 113(16):E2231-40. PMC: 4843487. DOI: 10.1073/pnas.1522556113. View

10.

Takayama K, Morisaki Y, Kuno S, Nagamoto Y, Harada K, Furukawa N . Prediction of interindividual differences in hepatic functions and drug sensitivity by using human iPS-derived hepatocytes. Proc Natl Acad Sci U S A. 2014; 111(47):16772-7. PMC: 4250156. DOI: 10.1073/pnas.1413481111. View

11.

Camenisch G, Umehara K . Predicting human hepatic clearance from in vitro drug metabolism and transport data: a scientific and pharmaceutical perspective for assessing drug-drug interactions. Biopharm Drug Dispos. 2012; 33(4):179-94. DOI: 10.1002/bdd.1784. View

12.

Marion M, Hantz O, Durantel D . The HepaRG cell line: biological properties and relevance as a tool for cell biology, drug metabolism, and virology studies. Methods Mol Biol. 2010; 640:261-72. DOI: 10.1007/978-1-60761-688-7_13. View

13.

Pettinato G, Lehoux S, Ramanathan R, Salem M, He L, Muse O . Generation of fully functional hepatocyte-like organoids from human induced pluripotent stem cells mixed with Endothelial Cells. Sci Rep. 2019; 9(1):8920. PMC: 6586904. DOI: 10.1038/s41598-019-45514-3. View

14.

Takebe T, Sekine K, Kimura M, Yoshizawa E, Ayano S, Koido M . Massive and Reproducible Production of Liver Buds Entirely from Human Pluripotent Stem Cells. Cell Rep. 2017; 21(10):2661-2670. DOI: 10.1016/j.celrep.2017.11.005. View

15.

Lin J, Schyschka L, Muhl-Benninghaus R, Neumann J, Hao L, Nussler N . Comparative analysis of phase I and II enzyme activities in 5 hepatic cell lines identifies Huh-7 and HCC-T cells with the highest potential to study drug metabolism. Arch Toxicol. 2011; 86(1):87-95. DOI: 10.1007/s00204-011-0733-y. View

16.

Takenaka T, Harada N, Kuze J, Chiba M, Iwao T, Matsunaga T . Application of a Human Intestinal Epithelial Cell Monolayer to the Prediction of Oral Drug Absorption in Humans as a Superior Alternative to the Caco-2 Cell Monolayer. J Pharm Sci. 2016; 105(2):915-924. DOI: 10.1016/j.xphs.2015.11.035. View

17.

Wang Y, Wang H, Deng P, Chen W, Guo Y, Tao T . In situ differentiation and generation of functional liver organoids from human iPSCs in a 3D perfusable chip system. Lab Chip. 2018; 18(23):3606-3616. DOI: 10.1039/c8lc00869h. View

18.

Pasca A, Sloan S, Clarke L, Tian Y, Makinson C, Huber N . Functional cortical neurons and astrocytes from human pluripotent stem cells in 3D culture. Nat Methods. 2015; 12(7):671-8. PMC: 4489980. DOI: 10.1038/nmeth.3415. View

19.

Sontheimer-Phelps A, Hassell B, Ingber D . Modelling cancer in microfluidic human organs-on-chips. Nat Rev Cancer. 2019; 19(2):65-81. DOI: 10.1038/s41568-018-0104-6. View

20.

Archer C, Sargeant R, Basak J, Pilling J, Barnes J, Pointon A . Characterization and Validation of a Human 3D Cardiac Microtissue for the Assessment of Changes in Cardiac Pathology. Sci Rep. 2018; 8(1):10160. PMC: 6033897. DOI: 10.1038/s41598-018-28393-y. View