Prediction of the Overall Renal Tubular Secretion and Hepatic Clearance of Anionic Drugs and a Renal Drug-Drug Interaction Involving Organic Anion Transporter 3 in Humans by In Vitro Uptake Experiments

ABSTRACTThe purpose of this study was to determine if the disposition of cefadroxil, an α-amino-containing β-lactam antibiotic, changes during lipopolysaccharide (LPS)-induced acute inflammation. Six hours after LPS or saline treatment, mice received 1 nmol/g cefadroxil intravenously along with inulin for glomerular filtration rate (GFR) determination. Serial blood samples, along with tissue and urine samples, were collected at predetermined time points. In order to determine inflammation-induced changes in GFR, renal tubular secretion, and reabsorption, it was necessary to coadminister 70 mg/kg probenecid. Changes in the expression of the mRNA of transporters involved in cefadroxil disposition in the kidneys and choroid plexus were also investigated 6 h after LPS treatment. The results demonstrated marked increases in blood, cerebrospinal fluid, and tissue cefadroxil concentrations with LPS treatment. Tissue-to-blood concentration ratios were decreased by 4.6-fold in the choroid plexus and by 2.5-fold in the kidneys during LPS-induced inflammation. Renal, but not choroid plexus, mRNA expression of peptide transporter 2, organic-anion transporter 1 (OAT1), OAT3, and multidrug resistance-associated protein 4 was mildly reduced in LPS-treated mice. The renal clearance of cefadroxil was substantially decreased by LPS treatment (3-fold). GFR was also reduced by 3-fold in LPS-treated mice, but no significant differences in the fractional reabsorption of cefadroxil and renal secretion once normalized by GFR were observed. These findings demonstrated that LPS-induced inflammation has a dramatic effect on the renal excretion of cefadroxil. It appears that changes in transporter expression played a minor role during LPS treatment but that renal dysfunction, associated with GFR reduction, was responsible for the substantial increase in plasma cefadroxil concentration-time profiles.

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Overlapping in vitro and in vivo specificities of the organic anion transporters OAT1 and OAT3 for loop and thiazide diuretics

AJP Renal Physiology ◽

10.1152/ajprenal.00528.2007 ◽

2008 ◽

Vol 294 (4) ◽

pp. F867-F873 ◽

Cited By ~ 86

Author(s):

Volker Vallon ◽

Timo Rieg ◽

Sun Young Ahn ◽

Wei Wu ◽

Satish A. Eraly ◽

...

Keyword(s):

Organic Anion ◽

Tubular Secretion ◽

Organic Anion Transporter ◽

Thiazide Diuretics ◽

Renal Secretion ◽

Altered Expression ◽

Anion Transporter ◽

Sites Of Action

Organic anion transporter (OAT) genes have been implicated in renal secretion of organic anions, but the individual in vivo contributions of OAT1 (first identified as NKT) and OAT3 remain unclear. Potential substrates include loop diuretics (e.g., furosemide) and thiazide diuretics (e.g., bendroflumethiazide), which reach their tubular sites of action mainly by proximal tubular secretion. Previous experiments in Oat1 knockout (−/−) mice revealed an almost complete loss of renal secretion of the prototypic organic anion p-aminohippurate (PAH) and a role of OAT1 in tubular secretion of furosemide (Eraly SA, Vallon V, Vaughn D, Gangoiti JA, Richter K, Nagle M, Monte JC, Rieg T, Truong DM, Long JM, Barshop BA, Kaler G, Nigam SK. J Biol Chem 281: 5072–5083, 2006). In this study we found that both furosemide and bendroflumethiazide inhibited mOat1- and mOat3-mediated uptake of a labeled tracer in Xenopus oocytes injected with cRNA, consistent with their being substrates for mouse OAT1 and OAT3. Experiments in Oat3−/− mice revealed intact renal secretion of PAH, but the dose-natriuresis curves for furosemide and bendroflumethiazide were shifted to the right and urinary furosemide excretion was impaired similar to the defect in Oat1−/− mice. Thus, whereas OAT1 (in contrast to OAT3) is the classic basolateral PAH transporter of the proximal tubule, both OAT1 and OAT3 contribute similarly to normal renal secretion of furosemide and bendroflumethiazide, and a lack of either one is not fully compensated by the other. Although microarray expression analysis in the kidneys of Oat1−/− and Oat3−/− mice revealed somewhat altered expression of a small number of transport-related genes, none were common to both knockout models. When searching for polymorphisms involved in human diuretic responsiveness, it may be necessary to consider both OAT1 and OAT3, among other genes.

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Polyethlyene Glycol 200 Can Protect Rats Against Drug-Induced Kidney Toxicity Through Inhibition of the Renal Organic Anion Transporter 3

Toxicological Sciences ◽

10.1093/toxsci/kfz186 ◽

2019 ◽

Vol 172 (1) ◽

pp. 155-166

Author(s):

Yi-Zhong Gu ◽

Xiaoyan Chu ◽

Robert Houle ◽

Katerina Vlasakova ◽

Kenneth A Koeplinger ◽

...

Keyword(s):

Organic Anion ◽

Kidney Injury ◽

Organic Anion Transporter ◽

Female Rats ◽

Polysorbate 80 ◽

Renal Transporters ◽

Anion Transporter ◽

Polyethylene Glycol 200 ◽

Organic Anion Transporter 3

Abstract MK-7680, a cyclic nucleotide prodrug, caused significant kidney tubule injury in female rats when administered orally at 1000 mg/kg/day for 2 weeks using 10% Polysorbate 80 as vehicle. However, kidney injury was absent when MK-7680 was administered at the same dose regimen using 100% Polyethylene Glycol 200 (PEG 200) as the vehicle. Subsequent investigations revealed that MK-7680 triphosphate concentrations in kidney were much lower in rats treated with MK-7680 using PEG 200 compared with 10% Polysorbate 80 vehicle, whereas plasma exposures of MK-7680 prodrug were similar. In vitro studies demonstrated that PEG 200 is an inhibitor of human renal uptake transporter organic anion transporter 3 (OAT3), of which MK-7680 is a substrate. Furthermore, PEG 200 and PEG 400 were found to interfere in vitro with human renal transporters OAT3, organic cation transporter (OCT) 2, multidrug resistance-associated protein (MRP) 2 and 4, and multidrug and toxin extrusion protein (MATE) 1 and 2K, but not OAT1. These results support a conclusion that PEG 200 may prevent MK-7680-induced kidney injury by inhibiting its active uptake into proximal tubular cells by OAT3. Caution should be exercised therefore when using PEGs as vehicles for toxicity assessment for compounds that are substrates of renal transporters.

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Organic anion transporter 3 (Oat3/Slc22a8) knockout mice exhibit altered clearance and distribution of penicillin G

AJP Renal Physiology ◽

10.1152/ajprenal.00319.2007 ◽

2007 ◽

Vol 293 (4) ◽

pp. F1332-F1341 ◽

Cited By ~ 68

Author(s):

Adam L. VanWert ◽

Rachel M. Bailey ◽

Douglas H. Sweet

Keyword(s):

Knockout Mice ◽

Drug Disposition ◽

Organic Anion ◽

Organic Anion Transporter ◽

Penicillin G ◽

Anion Transporter ◽

Organic Anion Transporter 3

The interaction of renal basolateral organic anion transporter 3 (Oat3) with commonly used pharmacotherapeutics (e.g., NSAIDs, β-lactams, and methotrexate) has been studied extensively in vitro. However, the in vivo role of Oat3 in drug disposition, in the context of other transporters, glomerular filtration, and metabolism, has not been established. Moreover, recent investigations have identified inactive human OAT3 polymorphisms. Therefore, this investigation was designed to elucidate the in vivo role of Oat3 in the disposition of penicillin G and prototypical substrates using an Oat3 knockout mouse model. Oat3 deletion resulted in a doubling of penicillin's half-life ( P < 0.05) and a reduced volume of distribution ( P < 0.01), together yielding a plasma clearance that was one-half ( P < 0.05, males) to one-third ( P < 0.001, females) of that in wild-type mice. Inhibition of Oat3 abolished the differences in penicillin G elimination between genotypes. Hepatic accumulation of penicillin was 2.3 times higher in male knockouts ( P < 0.05) and 3.7 times higher in female knockouts ( P < 0.001). Female knockouts also exhibited impaired estrone-3-sulfate clearance. Oat3 deletion did not impact p-aminohippurate elimination, providing correlative evidence to studies in Oat1 knockout mice that suggest Oat1 governs tubular uptake of p-aminohippurate. Collectively, these findings are the first to indicate that functional Oat3 is necessary for proper elimination of xenobiotic and endogenous compounds in vivo. Thus Oat3 plays a distinct role in determining the efficacy and toxicity of drugs. Dysfunctional human OAT3 polymorphisms or instances of polypharmacy involving OAT3 substrates may result in altered systemic accumulation of β-lactams and other clinically relevant compounds.

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