Investigation into the predominate mechanism of OAT1 inhibition (1064.15)

Abstract

Renal tubular drug secretion mediated by the organic anion transporter 1 (OAT1) is a potential site of drug‐drug interactions. A number of marketed drugs inhibit OAT1, but the mechanism by which they do so is not typically known. The purpose was to investigate the predominant mechanism by which therapeutic drugs inhibit OAT1. OAT1 was expressed in Chinese hamster ovary cells and 3H‐para‐aminohippurate was used as the substrate. The Kreb’s cycle intermediate alpha‐ketoglutarate (αKG) competitively inhibited OAT1 with a Ki value (5.4 μM) approximating its unbound plasma concentration. In the presence of αKG (5 μM) the potency of inhibition caused by probenecid, furosemide and ibuprofen decreased ~2‐fold (~2‐fold increase in IC50 values), whereas the potency of inhibition caused by telmisartan was unaffected. This led us to speculate that probenecid, furosemide and ibuprofen interact competitively with αKG and 3H‐para‐aminohippurate while telmisartan is a non‐competitive inhibitor. Probenecid, furosemide and ibuprofen all competitively inhibited OAT1 with Ki values of 10.5 μM, 17.8 μM and 3.1 μM, respectively. In contrast, telmisartan inhibited OAT1 by reducing the maximal transport rate without affecting the Michaelis constant, indicating a non‐competitive type inhibition (IC50 of value of 0.33 μM). Interestingly, wash‐out experiments showed that the inhibitory effect of telmisartan is quasi‐irreversible. These data show that OAT1 inhibition can occur through different kinetic mechanisms. The mechanism by which inhibitors reduce OAT1 activity could influence the magnitude of drug‐drug interactions at OAT1‐mediated renal tubular drug secretion. Supported by NSHRF.Grant Funding Source: Supported by Nova Scotia Health Research Foundation