RT Journal Article
SR Electronic
T1 The Development, Characterization, and Application of an OATP1B1 Inhibition Assay in Drug Discovery
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1641
OP 1648
DO 10.1124/dmd.111.042382
VO 40
IS 8
A1 Matthew G. Soars
A1 Patrick Barton
A1 Manfred Ismair
A1 Rachael Jupp
A1 Robert J. Riley
YR 2012
UL http://dmd.aspetjournals.org/content/40/8/1641.abstract
AB The pivotal role of organic anion-transporting polypeptide 1B1 (OATP1B1) in drug disposition has become clear over the last decade. Therefore, an OATP1B1 inhibition assay suitable for use within early drug discovery was developed and characterized. IC50 estimates for 10 literature compounds using pitavastatin and estradiol-17β-glucuronide as substrates were within 2-fold of each other. In addition, the IC50 estimates using pitavastatin uptake agreed well with literature values (r2 = 0.92, average fold error = 1.3). However, when estrone-3-sulfate was used, OATP1B1 inhibition was underpredicted by as much as 10-fold. A comparison of uptake in human hepatocytes and OATP1B1 inhibition showed a significant correlation (r2 = 0.53, P < 0.001) for more than 40 compounds. These data suggest that, for discrete chemical series, OATP1B1 inhibition data may be used as a surrogate for more costly and time-consuming uptake studies in hepatocytes. OATP1B1 inhibition data, determined for over 260 compounds representing both internal AstraZeneca and literature chemistry, were also used to generate a continuous in silico model. The robustness of the model was demonstrated by accurately predicting OATP1B1 inhibition for external test sets using 50 AstraZeneca compounds (root mean square error = 0.45) and 12 literature drugs (RMSE = 0.32). The most important molecular descriptors for the prediction of OATP1B1 inhibition were maximal hydrogen bonding strength followed by cLogP. This study has shown that a well validated OATP1B1 inhibition assay in conjunction with an in silico approaches has the potential to influence significantly the design-make-test cycle and subsequently reduce the propensity of OATP1B1 ligands.