Profiling gene expression dynamics underpinning conventional testing approaches to better inform pre-clinical evaluation of an age appropriate spironolactone formulation

Abstract

There is a need to accelerate paediatric formulation evaluation and enhance quality of early stage data in drug development to alleviate the information pinch point present between formulation development and clinical evaluation. This present work reports application of DNA microarrays as a high throughput screening tool identifying markers for prediction of bioavailability and formulation driven physiological responses. With a focus on enhancing paediatric medicine provision an oral liquid spironolactone suspension was formulated addressing a paediatric target product profile. Caco-2 cells cultured on transwell inserts were implemented in transport assays in vitro and DNA microarrays were used to examine gene expression modulation. Wistar rats were used to derive in vivo bioavailability data. In vitro, genomic and in vivo data sets were concurrently evaluated linking drug transport and the genomic fingerprint generated by spironolactone formulation exposure. Significant changes in gene expression are reported as a result of formulation exposure. These include genes coding for ATP-binding cassette (ABC) transporters, Solute carrier (SLC) transporters, Cytochrome P450 (CYP) enzymes and carboxylesterase enzymes. Genomic findings better inform pre-clinical understanding of pharmacokinetic and pharmacodynamic responses to spironolactone and its active metabolites than current in vitro drug transport assays alone.

Publication DOI: https://doi.org/10.1080/10837450.2020.1839496
Divisions: College of Health & Life Sciences > Aston Pharmacy School
College of Health & Life Sciences
College of Health & Life Sciences > Chronic and Communicable Conditions
Additional Information: This is an Accepted Manuscript of an article published by Taylor & Francis Group in Pharmaceutical Development and Technology on 20 Oct 2020, available online at: http://www.tandfonline.com/10.1080/10837450.2020.1839496. Funding: Biotechnology and Biological Sciences Research Council for funding a CASE award in partnership with Pharmaspec Ltd (Ref number: BB/H016716/1).
Uncontrolled Keywords: ABC transporters,CYP enzymes,Microarray,SLC transporters,carboxylesterase enzymes,paediatrics,Pharmaceutical Science
Full Text Link:
Related URLs: https://www.tan ... 50.2020.1839496 (Publisher URL)
http://www.scop ... tnerID=8YFLogxK (Scopus URL)
PURE Output Type: Article
Published Date: 2021
Published Online Date: 2020-10-20
Accepted Date: 2020-10-16
Submitted Date: 2020-06-29
Authors: Russell, Craig (ORCID Profile 0000-0003-3791-2161)
Hussain, Majad
Huen, David
Rahman, Ayesha S
Mohammed, Afzal (ORCID Profile 0000-0002-5212-3040)

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Version: Accepted Version

Access Restriction: Restricted to Repository staff only until 20 October 2021.


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