Organic Anion Transporting Polypeptides 1B1 and 1B3 Play an Important Role in Uremic Toxin Handling and Drug-Uremic Toxin Interactions in the Liver

Abstract

PURPOSE. Organic anion-transporting polypeptide (OATP) 1B1 and OATP1B3 contribute to hepatic uptake of numerous drugs. Thus, reduced OATP1B1 and OATP1B3 activity in chronic kidney disease (CKD) may have a major impact on the hepatic clearance of drugs. The effect of drug-uremic toxin interactions on OATP1B1 and OATP1B3 has not been well studied. In the present study, we examine the inhibitory effects of uremic toxins on OATP1B1 and OATP1B3 transport activity to evaluate the interactions between drugs and uremic toxins in patients with chronic kidney disease. METHODS. [3H]Estron-3-sulfate, [3H]taurocholate uptake and [3H]methotrexate by OATP1B1 and OATP1B3 expressing HEK293 cells were performed to evaluate the inhibitory effect of uremic toxins. To clarify whether the uremic toxins that interact with OATP1B1 and/or OATP1B3 were substrates for these transporters, we performed uptake studies. RESULTS. Four uremic toxins, kynurenic acid, indole-3-acetic acid, indoxyl sulfate, and p-cresol, inhibited OATP1B1- and OATP1B3-mediated transport in a concentration-dependent manner, with IC50 values of 180, 770, 2700, and 4600 µM, respectively, for OATP1B1 and 180, 1100, 1300, and 1700 µM, respectively, for OATP1B3. [3H]Methotrexate uptake by OATPs was also inhibited by the four uremic toxins in a dose-dependent manner. Uptake studies revealed that kynurenic acid is a substrate for both the OATP1B1 and OATP1B3. Moreover, OATP1B3 was involved in the transport of indoxyl sulfate. Indole-3-acetic acid and p-cresol were not significantly transported by OATP1B1 and OATP1B3. CONCLUSIONS. We showed that some uremic toxins inhibit OATP-mediated uptake in a concentration-dependent manner, and clarified OATPs contribution to uremic toxin handling in the liver. Thus, we provided basic information to estimate the inhibitory effects of uremic toxins on OATPs in CKD patients. These data suggest that the dose of drugs excreted via renal and non-renal pathways should be carefully adjusted in CKD patients.This article is open to POST-PUBLICATION REVIEW. Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page.

Microbiota-derived uremic retention solutes: perpetrators of altered nonrenal drug clearance in kidney disease

“…Microbiota-derived uremic toxins affect hepatic OATP1B1, OATP1B3, and OATP2B1 activity and expression [56,67–71]. For example, OATP1B1 and OATP1B3 transport of methotrexate is inhibited by kynurenic acid, indole-3-acetic acid, indoxyl sulfate and p-cresol in HEK293 cells [68]. Kynurenic acid has the strongest inhibitory effect.…”

Analysis of membrane transport mechanisms of endogenous substrates using chromatographic techniques

“…Indoxyl sulfate is a well‐known uremic toxin that interacts with organic anion transporters. Transport by SLC22A6, SLC22A8 and SLCO1B3 was determined using RP‐HPLC–UV (Enomoto et al, ), RP‐HPLC–FL (Fujita et al, ) and LC/ESI–MS/MS (Sato et al, ), respectively. From these studies, it is suggested that indoxyl sulfate is a substrate for not only renal transporters SLC22A6 and SLC22A8 but also hepatic transporter SLCO1B3.…”

“…From these studies, it is suggested that indoxyl sulfate is a substrate for not only renal transporters SLC22A6 and SLC22A8 but also hepatic transporter SLCO1B3. Kynurenic acid, which is a metabolite in the kynurenine pathway, was identified as a substrate for ABCC4, SLCO1B1 and SLCO1B3 using LC/ESI–MS/MS (Dankers et al, ; Sato et al, ; Table ). Transporter‐overexpressing membrane vesicles or cells were used for the assay.…”

“…Transporter‐overexpressing membrane vesicles or cells were used for the assay. Both positive ion SRM (Dankers et al, ) and negative ion SRM (Sato et al, ) have been used for kynurenic acid detection.…”

Drug Transporters and Na+/H+Exchange Regulatory Factor PSD-95/Drosophila Discs Large/ZO-1 Proteins

“…Many studies attribute uremic toxins, metabolic byproducts that accumulate in uremia, as a major cause of reduced drug transporter function in CKD (Barreto et al, 2014;Masereeuw et al, 2014). Uremic toxins are believed to competitively inhibit drug transport and to downregulate transporter expression (Reyes and Benet, 2011;Sato et al, 2014). However, uremic toxins do not begin to accumulate until end-stage renal disease and therefore may only explain changes in drug transporter function in patients with end-state renal disease.…”