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.
Highlights
Georg-August-Universität Göttingen, Humboldtallee 23, 37073 Göttingen, Germany; Institut für Physiologie & Pathophysiologie, Zentrum für biomedizinische Ausbildung und Forschung (ZBAF), Fakultät für Medizin, Universität Witten/Herdecke, Stockumer Str. 12, D-58453 Witten, Germany
A variety of pathogenic mechanisms play a role in drug-induced nephrotoxicity, including hemodynamic changes, glomerular disease, interstitial nephritis, direct cytotoxicity which may result in tubular cell death, and intratubular precipitation of drugs leading to obstructive nephropathy [1,2,3]
We have focused on selected organic anion transporters (OATs) drug substrates, for which clinically relevant tubulotoxicity and/or nephrolithiasis have been reported, and have attempted to assess the contribution of individual OATs to these processes in the context of additional proximal tubular transport pathways for the respective compounds
Summary
A variety of pathogenic mechanisms play a role in drug-induced nephrotoxicity, including hemodynamic changes, glomerular disease, interstitial nephritis, direct cytotoxicity which may result in tubular cell death, and intratubular precipitation of drugs leading to obstructive nephropathy [1,2,3]. A large number of secretory transporters in the renal proximal tubule, many of them polyspecific, contribute to high intratubular solute concentrations, and to exposure of the tubular epithelium to high intracellular levels of potential cytotoxins The latter may be further aggravated for compounds which are reabsorbed from the tubular fluid. The affinity of human OAT1 for the non-metabolizable analogue glutarate is high, with a Km of about 11 μM [18] Both OAT1 and OAT3 are likely to mediate influx of drugs into renal proximal tubular cells under in vivo conditions, even if not all of the cellular dicarboxylate may be readily available for exchange [17]. OAT4 (SLC22A11), localized at the apical side of the proximal tubule cells, is known to function as an exchanger for dicarboxylates, albeit with a low glutarate affinity (IC50 value 1.25 mM, determined at a substrate concentration of 50 nM)[21]. It has to be emphasized that MRP and possibly OATP family members present in the renal tubule epithelium are likewise probenecid-sensitive [24,25]
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