A novel multi-parametric high content screening assay in ciPTEC-OAT1 to predict drug-induced nephrotoxicity during drug discovery

Archives of Toxicology
Anna-Karin SjögrenJorrit J Hornberg

Abstract

Drug-induced nephrotoxicity is a major concern in the clinic and hampers the use of available treatments as well as the development of innovative medicines. It is typically discovered late during drug development, which reflects a lack of in vitro nephrotoxicity assays available that can be employed readily in early drug discovery, to identify and hence steer away from the risk. Here, we report the development of a high content screening assay in ciPTEC-OAT1, a proximal tubular cell line that expresses several relevant renal transporters, using five fluorescent dyes to quantify cell health parameters. We used a validation set of 62 drugs, tested across a relevant concentration range compared to their exposure in humans, to develop a model that integrates multi-parametric data and drug exposure information, which identified most proximal tubular toxic drugs tested (sensitivity 75%) without any false positives (specificity 100%). Due to the relatively high throughput (straight-forward assay protocol, 96-well format, cost-effective) the assay is compatible with the needs in the early drug discovery setting to enable identification, quantification and subsequent mitigation of the risk for nephrotoxicity.

References

Jan 1, 1979·Journal of Psychiatric Research·I C CampbellD L Murphy
May 1, 1992·Biopharmaceutics & Drug Disposition·A GrahnénB Lindström
Aug 1, 1990·The American Journal of Physiology·P S KellermanB A Molitoris
Jan 1, 1988·European Journal of Clinical Pharmacology·J DouchampsA Herchuelz
Dec 1, 1987·Journal of Pharmaceutical Sciences·A McBurneyJ W Ward
Jun 1, 1974·Clinical Pharmacology and Therapeutics·R E CutlerB M Kimpel
Oct 1, 1971·Toxicology and Applied Pharmacology·G F MossJ S Cox
May 1, 1981·Clinical Pharmacology and Therapeutics·K J HimmelsteinL A Sternson
Nov 1, 1996·The Annals of Pharmacotherapy·M L SanteiroL Wyble
May 13, 1999·Clinical Pharmacokinetics·I Mahmood, C Sahajwalla
Dec 29, 2000·Therapeutic Drug Monitoring·R Kitzes-CohenG Uretzky
Jan 26, 2002·Journal of Clinical Pharmacology·Ruth E StevensFrederick L Cone
Apr 18, 2002·Antimicrobial Agents and Chemotherapy·Nelly CastroJulio Sotelo
Feb 13, 2003·Journal of Clinical Monitoring and Computing·R RegenthalR Preiss
Jul 31, 2003·Drugs·Therese ChapmanStuart Noble
Sep 23, 2003·Drugs·Toni Dando, Greg Plosker
Nov 30, 2005·The American Journal of Pathology·Giuliano CiarimboliEberhard Schlatter
May 19, 2006·Journal of the American Society of Nephrology : JASN·Prasad Devarajan
Aug 26, 2006·Nature Clinical Practice. Nephrology·Devasmita Choudhury, Ziauddin Ahmed
Sep 26, 2006·Toxicology·Lawrence H LashHongliang Cai
Sep 11, 2007·Drug Discovery Today·James A Dykens, Yvonne Will
Jun 6, 2008·Toxicological Sciences : an Official Journal of the Society of Toxicology·Jinghai J XuDavid de Graaf
Oct 22, 2008·Toxicology and Applied Pharmacology·Colin D A BrownAnja Verhulst
Feb 25, 2009·Archives of Biochemistry and Biophysics·Minako YabukiTeruhiko Matsumiya
Dec 19, 2009·Handbook of Experimental Pharmacology·Thomas D Nolin, Jonathan Himmelfarb
Mar 16, 2011·Laboratory Investigation; a Journal of Technical Methods and Pathology·James J KohlerWilliam Lewis
Apr 7, 2011·Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America·Jakko van IngenMartin J Boeree

❮ Previous
Next ❯

Citations

Feb 19, 2020·Archives of Toxicology·Jan G HengstlerJorrit J Hornberg
Aug 29, 2020·Archives of Toxicology·Tim Brecklinghaus
Oct 31, 2019·Archives of Toxicology·João FariaRosalinde Masereeuw
Aug 12, 2019·Archives of Toxicology·David Feuerborn
Jul 22, 2019·Respiratory Research·Guanghui LiuTaylor S Cohen
Dec 12, 2019·Archives of Toxicology·Tim Brecklinghaus
May 30, 2020·Trends in Molecular Medicine·Daniele ZinkJackie Y Ying
May 30, 2021·Pediatric Nephrology : Journal of the International Pediatric Nephrology Association·Andrew M HallRobert J Unwin
Jan 16, 2022·Journal of the American Society of Nephrology : JASN·Julie BejoyLauren E Woodard

❮ Previous
Next ❯

Methods Mentioned

BETA
Assay

Software Mentioned

sci
kit learn
drc
HCS Studio
R
LysoTracker

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.