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

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 (IC50) 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 IC50) are acids (pKa ∼ 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.