Application of anin vitroOAT assay in drug design and optimization of renal clearance

Abstract

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. 2. In vitro inhibition assays were established for human OAT1 and rat Oat3 and rat in vivo 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. 3. Many of the compounds were actively secreted and in vitro analysis demonstrated that these were ligands for rat and human OAT transporters (IC50 values ranging from <1 to >100 µM). Application of resultant QSAR models reduced renal clearance in the rat from 24 to <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. 4. This study has demonstrated that OAT inhibition data and QSAR models can be successfully used to optimize rat renal clearance in vivo and provide confidence of translation to humans.

Optimization of Metabolic and Renal Clearance in a Series of Indole Acid Direct Activators of 5′-Adenosine Monophosphate-Activated Protein Kinase (AMPK)

“…At the outset, there was insufficient data for compounds in this class to show a strong correlation between active CL renal in rat and rat Oat3 (or human OAT3) transporter activity measured in vitro. Creating a data set to demonstrate the in vitro–in vivo correlation was an integral part of this work …”

Current Advances in Studying Clinically Relevant Transporters of the Solute Carrier (SLC) Family by Connecting Computational Modeling and Data Science

“… Tsigelny et al [ 112 ] OAT1 Molecular dynamics simulation Investigations of dynamics events accompanying OAT1 transport Tilting mechanism of two hemi-domains is crucial for the initialization of transport process. Soars et al [ 134 ] OAT1, OAT3 QSAR modeling Comparison of inhibitor features between OAT1 and OAT3 OAT1 and OAT3 inhibitors have statistically significant inhibitory profiles. Bednarczyk et al [ 135 ] OCT1 LB pharmacophore modeling Identification of important pharmacophoric features for OCT1 inhibition Three hydrophobic and one positive ionizable feature are important features for OCT1 inhibition.…”

Computational modeling to predict the functions and impact of drug transporters

“…The reasons for this are two-fold: P-gp is one of the most important transporters in the cellular protection and detoxificafion process and, because it was the first efflux transporter to be identified, a large body of experimental data is available. More recently, as experimental data are becoming available, the same types of modeling approach have been applied to other drug-transporting ABCs and SLCs, including BCRP (Matsson et al 2007 , Matsson et al 2009 ), MRP2 (Pedersen et al 2008 , Matsson et al 2009 ) OCT1 (Ahlin et al 2008 ), OCT2 (Suhre et al 2005 , Kido et al 2011 ) OATs (Truong et al 2008 , Soars et al 2014 ), OATPs (Karlgren et al 2012 , De Bruyn et al 2013 ) and MATE1 (Wittwer et al 2013 ).…”