Probenecid inhibits the renal clearance and renal glucuronidation of nalidixic acid

Vree, T. B.; Biggelaar-Martea, M. van den; Kolmer, E. W. J. Vann Ewijk-Beneken

doi:10.1007/bf01880560

Cited by 17 publications

(11 citation statements)

References 15 publications

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“…In particular, the renal elimination of a number of OAT substrates, including famotidine (Inotsume et al, 1990), cidofovir (Cundy et al, 1995), furosemide (Vree et al, 1995), and ciprofloxacin (Jaehde et al, 1995), is slowed in the presence of the well established OAT inhibitor probenecid. However, due to overlap in substrate selectivity between OAT1, OAT3, and other clearance mechanisms, such as metabolism and other transporters, it is difficult to solely implicate renal OATs in DDIs.…”

Section: Introductionmentioning

confidence: 99%

A Plasma Concentration of α-Ketoglutarate Influences the Kinetic Interaction of Ligands with Organic Anion Transporter 1

Ingraham

Renfro

et al. 2014

Mol Pharmacol

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The purpose of the present study was to determine whether a physiologic plasma concentration of a-ketoglutarate (aKG) influences the kinetic interaction of ligands with organic anion transporter 1 (OAT1). The effect of extracellular aKG on the kinetics of para-aminohippurate (PAH) and cidofovir transport was examined along with its effect on the potency of 10 drugs in five different classes (uricosuric, nonsteroidal anti-inflammatories, loop diuretics, angiotensin II receptor antagonists, and b-lactam antibiotics) to inhibit OAT1 expressed in Chinese hamster ovary cells. Extracellular aKG competitively inhibited PAH and cidofovir transport with K i values (∼5 mM) approximating its unbound plasma concentration (determined by equilibrium dialysis). When PAH was the substrate, extracellular aKG (5 mM) significantly increased IC 50 values for some inhibitors (up to 4-fold), such as probenecid, but not for others (an inhibitor-dependent effect). For some inhibitors, a significant increase in IC 50 value was observed when cidofovir was the substrate, but not PAH (a substrate-dependent effect). A significant increase in IC 50 value was also observed for inhibition of PAH transport by probenecid in renal basolateral membrane vesicles (5.2-fold). The substrate-and inhibitor-dependent effect of extracellular aKG on ligand interactions with OAT1 highlights the complexity of the OAT1 ligand-binding surface. The effect of extracellular aKG on the potency of OAT1 inhibition should be considered when assessing drug-drug interaction potential at the transporter.

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Section: Introductionmentioning

confidence: 99%

A Plasma Concentration of α-Ketoglutarate Influences the Kinetic Interaction of Ligands with Organic Anion Transporter 1

Ingraham

Renfro

et al. 2014

Mol Pharmacol

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“…In fact, co-administration of probenecid, a nonspecific inhibitor of organic anion transport systems, inhibits the renal elimination and diuretic action in humans (6,7).…”

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confidence: 99%

Multidrug Resistance–Associated Protein 4 Is Involved in the Urinary Excretion of Hydrochlorothiazide and Furosemide

Hasegawa

Kusuhara

Adachi

et al. 2007

Journal of the American Society of Nephrology

110

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The role of ATP-binding cassette transporters in the urinary excretion of diuretics was investigated. Significant ATPdependent uptake of hydrochlorothiazide (HCT) and furosemide was observed in membrane vesicles that expressed multidrug resistance-associated protein 4 (MRP4) and breast cancer resistance protein (BCRP). Unlike taurocholate uptake, S-methylglutathione had no effect on the ATP-dependent uptake of both compounds by MRP4. The functional importance of MRP4 and BCRP in the urinary excretion of HCT and furosemide was investigated using gene knockout mice. The renal clearance of HCT and furosemide was reduced significantly but not abolished in Mrp4 knockout mice compared with wild-type mice (9.0 ؎ 0.9 versus 15 ؎ 2 ml/min per kg for HCT and 1.9 ؎ 0.3 versus 2.7 ؎ 0.1 ml/min per kg for furosemide), and the amount of HCT that was associated with the kidney specimens was greater in Mrp4 knockout mice (21 ؎ 3 versus 13 ؎ 1 nmol/g kidney). In contrast, Bcrp makes only a negligible contribution because the urinary excretion was unchanged in Bcrp knockout mice. Our results suggest that Mrp4, together with other unknown transporters, accounts for the luminal efflux of HCT and furosemide from proximal tubular epithelial cells.

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“…This should be further confirmed by comparing in vivo pharmacokinetics in monkeys and humans. In addition to famotidine, inhibition of renal elimination by probenecid has been reported for benzylpenicillin (Overbosch et al, 1988), cephalosporins (Shitara et al, 2005), oseltamivir (its active metabolite Ro 64-0802) (Hill et al, 2002), furosemide (Vree et al, 1995), bumetanide (Lau et al, 1983), ciprofloxacin (Jaehde et al, 1995), enalapril/enalaprilat (Noormohamed et al, 1990), and fexofenadine (YasuiFurukori et al, 2005). Among these drugs, benzylpenicillin (Tahara et al, 2005), cephalosporins (Jung et al, 2002;Uwai et al, 2002), oseltamivir (its active metabolite Ro 64-0802) (Hill et al, 2002), furosemide, and bumetanide (Hasannejad et al, 2004) have been reported to be substrates of OAT1 and/or OAT3.…”

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confidence: 99%

A Species Difference in the Transport Activities of H₂Receptor Antagonists by Rat and Human Renal Organic Anion and Cation Transporters

Tahara

Kusuhara²,

Endou³

et al. 2005

J Pharmacol Exp Ther

157

115

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A clinical drug-drug interaction between famotidine (a H 2 receptor antagonist) and probenecid has not been reproduced in rats. The present study hypothesized that the species-dependent probenecid sensitivity is due to a species difference in the contribution of renal organic anion and cation transporters. The transport activities of the H 2 receptor antagonists (cimetidine, famotidine, and ranitidine) by rat and human basolateral organic anion and cation transporters [human organic anion transporter (hOAT) 1, hOAT2, r/hOAT3, rat organic cation transporter (rOct) 1, and r/hOCT2] were compared using their cDNA transfectants. The transport activities (V max /K m ) of famotidine (K m , 345 M) by rOat3 were 8-and 15-fold lower than those of cimetidine (K m , 91 M) and ranitidine (K m , 155 M), respectively, whereas the activity by hOAT3 (K m , 124 M) was 3-fold lower than that of cimetidine (K m , 149 M) but similar to that of ranitidine (K m , 234 M). Comparison of the relative transport activity with regard to that of cimetidine suggests that famotidine was more efficiently transported by hOAT3 than rOat3, and vice versa, for ranitidine. Only ranitidine was efficiently transported by hOAT2 (K m , 396 M). rOct1 accepts all of the H 2 receptor antagonists with a similar activity, whereas the transport activities of ranitidine and famotidine (K m , 61/56 M) by r/hOCT2 were markedly lower than that of cimetidine (K m , 69/73 M). Probenecid was a potent inhibitor of r/OAT3 (K i , 2.6 -5.8 M), whereas it did not interact with OCTs. These results suggest that, in addition to the absence of OCT1 in human kidney, a species difference in the transport activity by hOAT3 and rOat3 accounts, at least in part, for the species difference in the drug-drug interaction between famotidine and probenecid.The kidney plays important roles in the detoxification of xenobiotics and endogenous wastes as well as maintaining the correct balance of ions and nutrients in the body. Urinary excretion is the major detoxification mechanism in the kidney, and this is governed by glomerular filtration, tubular secretion across the proximal tubules, and reabsorption. The renal uptake of organic anions and cations on the basolateral membrane of the proximal tubules has been characterized by multispecific organic anion and cation transporters (OAT/ SLC22 and OCT/SLC22), respectively (Lee and Kim, 2004;Wright and Dantzler, 2004;Shitara et al., 2005).Molecular cloning of basolateral transporters from different species allows examination of differences in their substrate specificities and transport activities, leading to a better understanding of the molecular mechanisms of species differences in drug disposition. For OCTs, the isoform expressed in the kidney differs between rodents and humans. Both Oct1 (Slc22a1) and Oct2 (Slc22a2) are involved in the renal uptake of organic cations on the basolateral membrane of the proximal tubules in rodents, whereas OCT2 is the predominant isoform in the human kidney (Koepsell, 2004;Lee and Kim, 2004;Wright a...

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Probenecid inhibits the renal clearance and renal glucuronidation of nalidixic acid

Cited by 17 publications

References 15 publications

A Plasma Concentration of α-Ketoglutarate Influences the Kinetic Interaction of Ligands with Organic Anion Transporter 1

A Plasma Concentration of α-Ketoglutarate Influences the Kinetic Interaction of Ligands with Organic Anion Transporter 1

Multidrug Resistance–Associated Protein 4 Is Involved in the Urinary Excretion of Hydrochlorothiazide and Furosemide

A Species Difference in the Transport Activities of H₂Receptor Antagonists by Rat and Human Renal Organic Anion and Cation Transporters

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Probenecid inhibits the renal clearance and renal glucuronidation of nalidixic acid

Cited by 17 publications

References 15 publications

A Plasma Concentration of α-Ketoglutarate Influences the Kinetic Interaction of Ligands with Organic Anion Transporter 1

A Plasma Concentration of α-Ketoglutarate Influences the Kinetic Interaction of Ligands with Organic Anion Transporter 1

Multidrug Resistance–Associated Protein 4 Is Involved in the Urinary Excretion of Hydrochlorothiazide and Furosemide

A Species Difference in the Transport Activities of H2Receptor Antagonists by Rat and Human Renal Organic Anion and Cation Transporters

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A Species Difference in the Transport Activities of H₂Receptor Antagonists by Rat and Human Renal Organic Anion and Cation Transporters