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Aliases: HOAT1, PAHT, ROAT1 (OAT1); None (OAT3)
Gene names: Solute carrier family 22 member 6/8 (SLC22A6/8)
OAT1 and 3 are predominantly renal anion-exchanging antiporters responsible for the uptake of substrates from the blood into renal proximal tubular cells. OAT1 and 3 are among the several important drug transporters in kidney proximal tubules that maintain systemic levels of endogenous substrates (e.g. uric acid), and facilitate the active renal secretion of drugs into the urine. OAT1 and 3 have strongly overlapping substrate specificities; important drug substrates of both include penicillins, NSAIDs, methotrexate, HIV protease inhibitors, and antivirals. Inhibition of OATs results in reduced or delayed renal elimination. Drug substrates with narrow therapeutic indices (e.g. methotrexate) are of most concern for DDI. OATs are also implicated in some drug-induced renal toxicities.
The FDA and EMA regulatory guidances recommend evaluation of OAT transporter interactions for NCEs and circulating metabolites, particularly where significant renal elimination of negatively charged drugs is observed.
OAT1 and 3 have 12 predicted transmembrane domains and are primarily expressed in the basolateral (blood-side) membrane of proximal tubule cells in the kidney, with highest levels in the middle segment, and are considered as kidney-specific transporters in humans [1, 2]. Rat Oat1 has also been reported in the choroid plexus, skeletal muscle, and placenta [1, 3], while extrarenal rat Oat3 was only found in the choroid plexus [4, 5].
Function, physiology, and clinically significant polymorphisms
OAT1 and 3 are multispecific exchangers or antiporters that transport predominantly anionic substrates against a concentration gradient from the blood into proximal tubule cells for subsequent elimination into the urine. Uptake of substrates is dependent on the outwardly-directed concentration gradient of dicarboxylates (e.g. α-ketoglutarate). Exported intracellular dicarboxylates are replenished by the action of NaDC (SLC13A3), a sodium-dicarboxylate co-transporter which, in turn, relies on the sodium gradient maintained by sodium-potassium ATPase. This type of transport mechanism is often referred to as tertiary active transport.
OAT1 and 3, in conjunction with other uptake (e.g. OAT4, URAT1) and efflux (e.g. MRPs) transporters, belong to a suite of renal transporters whose function is to maintain circulating levels of endogenous anionic substances (e.g. uric acid) which might otherwise accumulate in the body. OAT1 and 3 constitute the first step in the active urinary excretion of circulating anionic xenobiotics and metabolites.
OAT1/3 substrates are typically smaller, negatively charged molecules and include antibiotics – especially beta-lactams and cephalosporins –, antivirals, histamine H2 receptor antagonists, diuretics, non-steroidal anti-inflammatory drugs (NSAIDs), statins, uricosurics, methotrexate, and toxins such as ochratoxin A. OAT1 also transports some neutral and cationic compounds (e.g., cimetidine), but with a lower affinity [6-8]. A key physiological role for OAT1/3 is the transport of over 35 uremic toxins and solutes, with varying preferences, including the gut-derived metabolites indole-3-acetic acid, 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) and phenylsulfate [9, 10]. OAT1 and 3 share many common substrates and inhibitors, and are generally both implicated in DDIs. The classical clinical inhibitor of OAT1/3 is the uricosuric drug probenecid (which is also a substrate). Other inhibitors include rifampicin, novobiocin, and the HIV integrase inhibitor cabotegravir . Numerous natural phenylpropanoids and flavonoids found in common dietary and herbal supplements, such as wogonin and wedelolacton, are also capable of inhibiting OAT1 (21 compounds) and OAT3 (45 compounds) . The β-lactam penicillin antibiotic cloxacillin was also shown to be both a substrate and a clinically relevant inhibitor of OAT3, but not OAT1, in overexpressing HEK293 cells .
Studies in kidney slices from Oat3-/- mice showed reduced renal taurocholate, estrone-3-sulfate, and PAH concentrations relative to the wild-types, with no differences in the liver, which does not express Oat3 . Penicillin PK was reduced by half in Oat3-/- male mice, and by two-thirds in female Oat3-/- mice , indicating gender-related differences that were also observed in methotrexate clearance . Gender-based differences in OAT3 have not been reported in humans.
While SNPs have been identified in the SLC22A6 gene, these are non-coding and do not translate into clinically significant drug-drug interactions . For example, rs10792367, an intergenic polymorphism between OAT1 and OAT3, is involved in antihypertensive responses to hydrochlorothiazide but not in transport activity . Similarly, there are limited reports on polymorphisms of SLC22A8, and few are of clinical relevance. OAT3 variants were identified from 270 ethnically diverse donor kidneys, but only three of these had allele frequencies greater than 1% . In a study with 120 healthy individuals, one non-synonymous variant was observed in the OAT3 gene, but this did not result in a change in renal clearance or pharmacokinetics of pravastatin , whereas the OAT3 p.I305F variant was associated with reduced cephalosporin clearance .
OAT1 transporter expression is regulated by LXR (downregulation) , hepatocyte nuclear factor 1 α/β, and DNA methylation . OAT1 transporter expression may be modulated by disease states; e.g., increased Oat1 expression is found in rats with bilateral ureteral obstruction  and chronic renal failure induced by nephrectomy can decrease OAT1 expression . OAT3 expression is transactivated by HNF1α/β, and OAT3 promoter activity is repressed by DNA methylation . The anti-cancer drugs carfilzomib and bortezomib inhibit proteasomes, thus preventing the degradation of ubiquitinated OAT1 which results in enhanced OAT1 expression and transport activity .
OAT1 and 3 are implicated in both DDIs and in renal toxicology due to drug exposure. Drugs predominantly eliminated by renal OATs include antivirals (e.g. oseltamivir) and olmesartan [27, 28]. Renal tubular secretion of drugs is inhibited by the co-administration of probenecid which, by simultaneous inhibition of OAT1 and 3, increases the circulating levels of OAT substrates such as penicillin, cephalosporin, pravastatin, fexofenadine, and some antiviral drugs by 10-260% [1, 29-31]. Mercuric conjugates, too, are transported by OAT1 and 3, contributing to the renal toxicity of these compounds , and OAT1 polymorphisms may influence urinary mercury concentrations in exposed individuals .
Probenecid can be used to reduce nephrotoxicity of therapeutics by inhibiting transport of potentially nephrotoxic drugs into the renal proximal tubular cells. Both cidofovir and cephaloridine are toxic to proximal tubular cells, and co-administration with probenecid results in reduced nephrotoxicity .
Modulation of OAT1/3 expression in disease conditions can modify the renal excretion of substrate drugs. Decrease in renal secretion and clearance may produce an increase in systemic drug exposure, thereby resulting in clinically significant changes in the overall drug PK. Clinically relevant changes in the clearance of therapeutics can occur when OAT1/3 transporter activity is inhibited.
OAT1 and 3 constitute the first step in the active renal tubular secretion of negatively charged drugs and metabolites, and are thus implicated in renal DDIs and toxicology. Therefore, the FDA and EMA regulatory guidances recommend evaluation of OAT transporter interactions for NCEs and circulating metabolites, particularly where significant renal elimination of negatively charged drugs is observed.
|Location||Endogenous substrates||In vitro substrates used experimentally||Substrate drugs||Inhibitors|
tubule basolateral membrane; placenta
|cyclic nucleotides, prostaglandin E2 and F2α, uric acid, folates, uremic toxins (e.g., indole-3-acetic acid, CMPF, phenylsulfate)||para-aminohippurate (PAH), adefovir, tenofovir, cidofovir||adefovir, zidovudine, cefaclor, ceftizoxime, cephaloridine, ciprofloxacin, famotidine, furosemide, ganciclovir, methotrexate, oseltamivir,carboxylate, penicillin G pravastatin||
rifampicin,tenofovir, cabotegravir, cloxacillin, benzylpenicillin, teriflunomide
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