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Identification and Quantitative Assessment of Uremic Solutes as Inhibitors of Renal Organic Anion Transporters, OAT1 and OAT3
journal contribution
posted on 2016-07-28, 00:00 authored by Chia-Hsiang Hsueh, Kenta Yoshida, Ping Zhao, Timothy
W. Meyer, Lei Zhang, Shiew-Mei Huang, Kathleen M. GiacominiOne
of the characteristics of chronic kidney disease (CKD) is the
accumulation of uremic solutes in the plasma. Less is known about
the effects of uremic solutes on transporters that may play critical
roles in pharmacokinetics. We evaluated the effect of 72 uremic solutes
on organic anion transporter 1 and 3 (OAT1 and OAT3) using a fluorescent
probe substrate, 6-carboxyfluorescein. A total of 12 and 13 solutes
were identified as inhibitors of OAT1 and OAT3, respectively. Several
of them inhibited OAT1 or OAT3 at clinically relevant concentrations
and reduced the transport of other OAT1/3 substrates in vitro. Review of clinical studies showed that the active secretion of most
drugs that are known substrates of OAT1/3 deteriorated faster than
the renal filtration in CKD. Collectively, these data suggest that
through inhibition of OAT1 and OAT3, uremic solutes contribute to
the decline in renal drug clearance in patients with CKD.