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

Craig Russell*, Majad Hussain, David Huen, Ayesha S Rahman, Afzal Mohammed*

*Corresponding author for this work

Research output: Contribution to journalArticle

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.
Original languageEnglish
JournalPharmaceutical Development and Technology
Early online date20 Oct 2020
DOIs
Publication statusE-pub ahead of print - 20 Oct 2020

Bibliographical note

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).

Keywords

  • Microarry
  • Paediatrics
  • ABC transporters
  • SLC Transporters
  • CYP enzymes
  • carboxylesterase enzymes

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