Assessment of the Role of Renal Organic Anion Transporters in Drug-Induced Nephrotoxicity

Abstract

In the present review we have attempted to assess the involvement of the organic anion transporters OAT1, OAT2, OAT3, and OAT4, belonging to the SLC22 family of polyspecific carriers, in drug-induced renal damage in humans. We have focused on drugs with widely recognized nephrotoxic potential, which have previously been reported to interact with OAT family members, and whose underlying pathogenic mechanism suggests the participation of tubular transport. Thus, only compounds generally believed to cause kidney injury either by means of direct tubular toxicity or crystal nephropathy have been considered. For each drug, or class of agents, the evidence for actual transport mediated by individual OATs under in vivo conditions is discussed. We have then examined their role in the context of other carriers present in the renal proximal tubule sharing certain substrates with OATs, as these are critical determinants of the overall contribution of OAT-dependent transport to intracellular accumulation and transepithelial drug secretion, and thus the impact it may have in drug-induced nephrotoxicity.

Human liver-kidney model elucidates the mechanisms of aristolochic acid nephrotoxicity

“…39), whereas OAT4 is typically expressed in the apical membrane. The lumen of kidney cells in our MPS model is oriented such that AA-I and other compounds have direct exposure to the apical membrane of the proximal tubule cells.…”

Flavonoids Are Inhibitors of Human Organic Anion Transporter 1 (OAT1)–Mediated Transport

“…It should be noted that, in addition to OAT1, OAT3 is also highly expressed in kidney and actively involved in the tubular uptake of various anionic xenobiotics (Burckhardt, 2012;Wang and Sweet, 2013b). In addition, OAT3 has also been found to play an important role in drug-induced nephrotoxicity (Hagos and Wolff, 2010). As OAT1 and OAT3 have substantial overlap in substrates and modulators (Rizwan and Burckhardt, 2007;Wang and Sweet, 2013b), and considering the potent inhibitory effect of flavonoids on OAT1, we anticipate that these flavonoids may also inhibit OAT3.…”

“…OAT1 is known to play a central role in the renal uptake of a wide range of anionic xenobiotics, including endogenous metabolic waste products, environmental toxins, and numerous clinically important drugs (e.g., antibiotics, antivirals, anti-inflammatory drugs, diuretics, and anticancer agents) (Rizwan and Burckhardt, 2007;Burckhardt, 2012;Wang and Sweet, 2013b). In addition, OAT1 is involved in the development of nephrotoxicity of many anionic xenobiotics (Hagos and Wolff, 2010). Consequently, preloading of OAT1 inhibitors, including probenecid, betamiprone, and NSAIDs, has been reported to reduce OAT1-mediated drug nephrotoxicity (Tune et al, 1977;Hirouchi et al, 1994;Lacy et al, 1998;Mulato et al, 2000).…”

“…Indeed, OAT1 has been reported to be involved, at least partly, in the emergence of the nephrotoxicity of several anionic xenobiotics, including b-lactam antibiotics (e.g., cephaloridine, cephaloglycin, and imipenem), antiviral agents (e.g., cidofovir and adefovir), as well as toxins (e.g., aristolochic acid and mercury) (Hagos and Wolff, 2010;Xue et al, 2011). For example, cephaloridine, a first-generation cephalosporin antibiotic, is rapidly transported into the proximal tubular cell by OATs, including OAT1, but undergoes minimal subsequent movement into the luminal fluid.…”

Acyclovir Dosing and Acute Kidney Injury: Deviations and Direction

“…12 Additionally, acyclovir and beta-lactam antibiotics (with varying affinities) are substrates for specific organic acid transporters (OAT1 and OAT3) that are present in the basolateral surface of the renal tubular cell and whose contribution to tubular cell uptake and excretion of these and many other drugs is under genetic control. 13 Benzylpenicillin reduced the rat renal acyclovir clearance via diminished tubular secretion resulting in an increased area-under the curve, and doubled the elimination half-life and mean residence time. The in-vitro affinity of uptake by OAT in kidney slices and transfected cells was markedly reduced when benzylpenicillin was co-administered.…”