The mechanism by which drugs inhibit organic anion transporter 1 (OAT1) was examined. OAT1 was stably expressed in Chinese hamster ovary (CHO) cells, and para-aminohippurate (PAH) and 6-carboxyfluorescein were the substrates. Most compounds (10 of 14) inhibited competitively, increasing the Michaelis constant (K m ) without affecting the maximal transport rate (J max ). Others were mixed-type (lowering J max and increasing K m ) or noncompetitive (lowering J max only) inhibitors. The interaction of a noncompetitive inhibitor (telmisartan) with OAT1 was examined further. Binding of telmisartan to OAT1 was observed, but translocation was not. Telmisartan did not alter the plasma membrane expression of OAT1, indicating that it lowers J max by reducing the turnover number. PAH transport after telmisartan treatment and its washout recovered faster in the presence of 10% fetal bovine serum in the washout buffer, indicating that binding of telmisartan to OAT1 and its inhibitory effect are reversible. Together, these data suggest that telmisartan binds reversibly to a site distinct from substrate and stabilizes the transporter in a conformation unfavorable for translocation. In the absence of an exchangeable extracellular substrate, PAH efflux from CHO-OAT1 cells was relatively rapid. Telmisartan slowed PAH efflux, suggesting that some transporter-mediated efflux occurs independent of exchange. Although drug-drug interaction predictions at OAT1 assume competitive inhibition, these data show that OAT1 can be inhibited by other mechanisms, which could influence the accuracy of drug-drug interaction predictions at the transporter. Telmisartan was useful for examining how a noncompetitive inhibitor can alter OAT1 transport activity and for uncovering a transport mode independent of exchange.

Intestinal and hepatic bile acid transporters are important for enterohepatic bile acid circulation and pharmacokinetics. Based on previous literature, we hypothesized that the expression of bile acid transporters and intestinal bile acid absorption are lower in older individuals. Here, we measured active taurocholate absorption across the ileum of male C57BL/6 mice in two different age cohorts – young (age range of 89–224 days) and old (age range of 613–953 days). Also examined in these mice were mRNA expression of the major bile acid transporters – Asbt and Ostα/β in the ileum, and Ntcp, Oatp1b2 and Bsep in the liver. Mean intestinal taurocholate absorption was significantly lower (~50%) in mice in the older cohort compared to those in the younger cohort. In the ileum, the expression of Asbt was significantly lower in the older cohort, but expression of Ostα/β was not affected by age. The lower capacity for intestinal bile acid absorption in the older animals is consistent with their lower expression level of Asbt. Of the hepatic bile acid transporters examined, expression of Ntcp and Oatp1b2 were significantly lower in the older mice. This is the first study to directly measure intestinal bile acid absorption as a function of age. The data suggest a lower capacity for intestinal bile acid absorption in older animals. Also, lower expression of Asbt, Ntcp, and Oatp1b2 in older individuals could influence pharmacokinetics of drug substrates.