Renal tubular mechanisms for creatinine secretion in the guinea pig

Arendshorst, WJ; Ee, Selkurt

doi:10.1152/ajplegacy.1970.218.6.1661

Cited by 15 publications

(7 citation statements)

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“…A possible explanation could be that cimetidine has both a high affinity for the cation transport system and a low affinity for the anion transport sys tem. Similar observations were made for cre atinine [21], adrenaline [22] and noradrena line [23], which are evidently transported by both pathways. However, in our experimental approach changes in intracellular parameters such as electrolyte content or the membrane potential may occur and may also influence transport processes.…”

Section: Discussionsupporting

confidence: 85%

Transport of Cimetidine across the Basolateral Membrane of Rabbit Kidney Proximal Tubules: Interaction with Organic Anions

Brändle

Greven²

1992

Pharmacology

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Since in whole animal studies and in man the renal clearance of cimetidine was prolonged by the coadministration of probenecid, the aim of the present study was to examine the interaction of the organic base cimetidine with the organic anion transport system at the basolateral membrane of isolated non-perfused rabbit proximal tubules. S₂ segments of proximal tubules were incubated at 37.5 °C with ³H-cimetidine (2 × 10^–7 mol/l) or ³H-PAH (4 × 10^–6 mol/l, as a marker for the organic anion transport system) and ¹⁴C-inulin (marker for the extracellular space) for 25 min to achieve a steady state. Afterwards, a nonradiolabelled substance was added to the bath, and the change of the cellularly stored radioactivity was measured at 5-min intervals. Probenecid (5 × 10^–5 mol/l) decreased the cellular amount of ³H-cimetidine to 26% of the control value. At this concentration, furosemide and Na₂SO₄ had no effect. At a concentration of 10^-3 mol/l, these substances reduced the cellular ³H-cimetidine uptake to 33% (furosemide) and 57% (Na₂SO₄) of the control value. 10^–4 and 10^–3 mol/l succinate diminished the steady-state uptake of cimetidine to 77% and 53% of the control value, respectively. On the other hand, cimetidine (10^–3 mol/l) decreased the cellular uptake of ³H-PAH to 52% of the control value. N1-Meth-ylnicotinamide (5 × 10^–5 mol/l and 10^–3 mol/l) had no effect on the steady-state uptake of ³H-PAH. These results indicate that the organic base cimetidine, besides its high affinity for the cation transporter, also interacts with the organic anion transport system at the basolateral membrane of rabbit proximal tubules.

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Section: Discussionsupporting

confidence: 85%

Transport of Cimetidine across the Basolateral Membrane of Rabbit Kidney Proximal Tubules: Interaction with Organic Anions

Brändle

Greven²

1992

Pharmacology

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“…19 Supporting a role of anionic transporters in creatinine secretion across species, inhibitors of anionic transporters have been noted to affect renal creatinine secretion in a number of species including humans. 22, 23, 29, 30, 31, 32, 33, 34 Adding further support for the role of anion transporters in creatinine secretion, Vallon et al 23 found that mouse Oat1 and Oat3 can transport creatinine in vitro , that this transport was inhibited by cimetidine, and that Oat3-knockout mice had blunted creatinine secretion in vivo . While providing a more comprehensive understanding of the role of Oat3 in creatinine secretion in mice, species differences in transporter expression and substrate specificity may affect the relevance of this finding to humans.…”

Section: Discussionmentioning

confidence: 95%

Contribution of the organic anion transporter OAT2 to the renal active tubular secretion of creatinine and mechanism for serum creatinine elevations caused by cobicistat

Lepist

Zhang

Jia

et al. 2014

Kidney International

214

191

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Many xenobiotics including the pharmacoenhancer cobicistat increase serum creatinine by inhibiting its renal active tubular secretion without affecting the glomerular filtration rate. This study aimed to define the transporters involved in creatinine secretion, applying that knowledge to establish the mechanism for xenobiotic-induced effects. The basolateral uptake transporters organic anion transporter OAT2 and organic cation transporters OCT2 and OCT3 were found to transport creatinine. At physiologic creatinine concentrations, the specific activity of OAT2 transport was over twofold higher than OCT2 or OCT3, establishing OAT2 as a likely relevant creatinine transporter and further challenging the traditional view that creatinine is solely transported by a cationic pathway. The apical multidrug and toxin extrusion transporters MATE1 and MATE2-K demonstrated low-affinity and high-capacity transport. All drugs known to affect creatinine inhibited OCT2 and MATE1. Similar to cimetidine and ritonavir, cobicistat had the greatest effect on MATE1 with a 50% inhibition constant of 0.99 μM for creatinine transport. Trimethoprim potently inhibited MATE2-K, whereas dolutegravir preferentially inhibited OCT2. Cimetidine was unique, inhibiting all transporters that interact with creatinine. Thus, the clinical observation of elevated serum creatinine in patients taking cobicistat is likely a result of OCT2 transport, facilitating intracellular accumulation, and MATE1 inhibition.

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“…In fact, renal creatinine secretion in guinea pig (3) and rat (9,17) can be inhibited by probenecid, a prototypical inhibitor of organic anion transport (OAT). This occurred at physiological (9) as well as increased creatinine plasma levels (14,17).…”

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confidence: 99%

A role for the organic anion transporter OAT3 in renal creatinine secretion in mice

Vallon

Eraly

Rao

et al. 2012

American Journal of Physiology-Renal Physiology

104

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Tubular secretion of the organic cation, creatinine, limits its value as a marker of glomerular filtration rate (GFR) but the molecular determinants of this pathway are unclear. The organic anion transporters, OAT1 and OAT3, are expressed on the basolateral membrane of the proximal tubule and transport organic anions but also neutral compounds and cations. Here, we demonstrate specific uptake of creatinine into mouse mOat1- and mOat3-microinjected Xenopus laevis oocytes at a concentration of 10 μM (i.e., similar to physiological plasma levels), which was inhibited by both probenecid and cimetidine, prototypical competitive inhibitors of organic anion and cation transporters, respectively. Renal creatinine clearance was consistently greater than inulin clearance (as a measure of GFR) in wild-type (WT) mice but not in mice lacking OAT1 ( Oat1−/−) and OAT3 ( Oat3−/−). WT mice presented renal creatinine net secretion (0.23 ± 0.03 μg/min) which represented 45 ± 6% of total renal creatinine excretion. Mean values for renal creatinine net secretion and renal creatinine secretion fraction were not different from zero in Oat1−/− (−0.03 ± 0.10 μg/min; −3 ± 18%) and Oat3−/− (0.01 ± 0.06 μg/min; −6 ± 19%), with greater variability in Oat1−/−. Expression of OAT3 protein in the renal membranes of Oat1−/− mice was reduced to ∼6% of WT levels, and that of OAT1 in Oat3−/− mice to ∼60%, possibly as a consequence of the genes for Oat1 and Oat3 having adjacent chromosomal locations. Plasma creatinine concentrations of Oat3−/− were elevated in clearance studies under anesthesia but not following brief isoflurane anesthesia, indicating that the former condition enhanced the quantitative contribution of OAT3 for renal creatinine secretion. The results are consistent with a contribution of OAT3 and possibly OAT1 to renal creatinine secretion in mice.

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Renal tubular mechanisms for creatinine secretion in the guinea pig

Cited by 15 publications

References 0 publications

Transport of Cimetidine across the Basolateral Membrane of Rabbit Kidney Proximal Tubules: Interaction with Organic Anions

Transport of Cimetidine across the Basolateral Membrane of Rabbit Kidney Proximal Tubules: Interaction with Organic Anions

Contribution of the organic anion transporter OAT2 to the renal active tubular secretion of creatinine and mechanism for serum creatinine elevations caused by cobicistat

A role for the organic anion transporter OAT3 in renal creatinine secretion in mice

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