Application of an in vitro OAT assay in drug design and optimization of renal clearance. (July 2014)

• Record Type: Journal Article
• Authors: Soars, Matthew G.; Barton, Patrick; Elkin, Lisa L.; Mosure, Kathleen W.; Sproston, Joanne L.; Riley, Robert J.
• Is Part Of: Xenobiotica. Volume 44:Number 7(2014:Jul.)
• Page Start: 657
• Page End: 665
• Publication Date: 2014-07
• Subjects: Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.3109/00498254.2013.879625
• Languages: English
• ISSNs: 0049-8254

Abstract

<abstract> <title>Abstract</title> <p>1. Optimization of renal clearance is a complex balance between passive and active processes mediated by renal transporters. This work aimed to characterize the interaction of a series of compounds with rat and human organic anion transporters (OATs) and develop quantitative structure–activity relationships (QSARs) to optimize renal clearance.</p> <p>2<italic>. In vitro</italic> inhibition assays were established for human OAT1 and rat Oat3 and rat <italic>in vivo</italic> renal clearance was obtained. Statistically significant quantitative relationships were explored between the compounds' physical properties, their affinity for OAT1 and oat3 and the inter-relationship with unbound renal clearance (URC) in rat.</p> <p>3. Many of the compounds were actively secreted and <italic>in vitro</italic> analysis demonstrated that these were ligands for rat and human OAT transporters (IC₅₀ values ranging from &lt;1 to &gt;100 µM). Application of resultant QSAR models reduced renal clearance in the rat from 24 to &lt;0.1 ml/min/kg. Data analysis indicated that the properties associated with increasing affinity at OATs are the same as those associated with reducing URC but orthogonal in nature.</p> <p>4. This study has demonstrated that OAT inhibition data and QSAR models can be successfully used to optimize rat renal clearance <italic>in vivo</italic> and provide confidence of translation to humans.</p> </abstract>