Identification of Organic Anion Transporter 2 Inhibitors: Screening, Structure-Based Analysis, and Clinical Drug Interaction Risk Assessment

Abstract

Organic anion transporter 2 (OAT2 or SLC22A7) plays an important role in the hepatic uptake and renal secretion of several endogenous compounds and drugs. The goal of this work is to understand the structure activity of OAT2 inhibition and assess clinical drug interaction risk. A single-point inhibition assay using OAT2-transfected HEK293 cells was employed to screen about 150 compounds; and concentration-dependent inhibition potency (IC 50 ) was measured for the identified "inhibitors". Acids represented about 65% of all inhibitors, and the frequency of bases-plus-zwitterions approximately doubled for "non-inhibitors". Interestingly, 9 of 10 most potent inhibitors (low IC 50 ) are acids (pK a ∼ 3−5). Additionally, inhibitors are significantly larger and lipophilic than non-inhibitors. In silico (binary) models were developed to identify inhibitors and non-inhibitors. Finally, in vivo risk assessed via static drug−drug interaction models identified several inhibitors with potential for renal and hepatic OAT2 inhibition at clinical doses. This is the first study assessing the global pattern of OAT2−ligand interactions.

Significance of Organic Anion Transporter 2 and Organic Cation Transporter 2 in Creatinine Clearance: Mechanistic Evaluation Using Freshly Prepared Human Primary Renal Proximal Tubule Cells

“…Clinically relevant OAT2 inhibitors are limited and there is no direct in vivo evidence to associate OAT2mediated transport to CrCL. Of the identified OAT2 inhibitors, indomethacin has potential to inhibit OAT2 transport in vivo with the estimated maximal unbound plasma concentration (I max,u )/IC 50 ratio (~0.30) at 50 mg dose (I max,u , 0.67µM (Ryu et al, 2022); IC 50 , 2.34µM (Table 1)) that is above the recommended in vivo inhibition risk criteria (Europen Medicines Agency, 2012; US Food & Drug Administration , 2020). However, no change was noted in CrCL with indomethacin 25 mg t.i.d.…”