Facilitation by serum albumin of renal tubular secretion of organic anions

Besseghir, Kamel; Mosig, Dolores; Roch-Ramel, F

doi:10.1152/ajprenal.1989.256.3.f475

Cited by 26 publications

(40 citation statements)

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“…In contrast with what was found in rabbit renal proximal tubules for p-aminohippurate (Besseghir et al 1989), BSA did not enhance tubular secretion of this hippurate analogue. Our results show that kidney:perfusate ratios did increase in 4 presence of BSA at low perfusate concentration, however; this could be explained by a strongly reduced free concentration of 2-methylbenzoylgIycine in perfusate rather than a stimulatory effect of BSA.…”

Section: Renal Excretion and Accumulationcontrasting

confidence: 99%

“…Because of the efficiency of the secretory process, the renal extraction ratio practically equals 1, indicating that renal clearance and accumulation are insensitive to changes in protein binding and only influenced by changes in renal blood flow (Grantham & Chonko 1991;Levy 1980). The presence of serum protein, on the other hand, may even facilitate paminohippurate secretion (Besseghir et al 1989). Plasma protein binding of this compound is, however, low (Russel et al 1989b).…”

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confidence: 99%

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Renal Excretion and Accumulation Kinetics of 2-Methylbenzoylglycine in the Isolated Perfused Rat Kidney

Masereeuw

Moons

Rüssel

1996

Journal of Pharmacy and Pharmacology

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The effect of protein binding on kidney function has been studied by investigating the renal accumulation and secretion of the hippurate analogue 2-methylbenzoylglycine in the isolated perfused rat kidney in the absence and presence of bovine serum albumin (BSA), Experiments were performed with either 2-5% pluronic or a combination of 2-2% pluronic and 2% BSA as oncotic agents; a wide concentration range (1-190 fig inL~1) of 2-methylbenzoylglycine was studied. Tubular secretion appeared to be a function of the amount of unbound drug in the perfusate and was best described by a model consisting of a high and low affinity Michaelis-Menten term. Parameters obtained after the analysis^of renal excretion data were maximum transport velocity for the high affinity site (TM iH ) -3 -0 db 2-8 fig min" , Michaelis-Menten constant for tubular transport for the high affinity site (KTfH ) = 0-5 ± 0-8 fig mL , maximum transport velocity for the low affinity site ^, 0 -2503:36 ¿¿g_min~ , and Michaelis-Menten constant for tubular transport for the low affinity site ( K T(l ) = 62 ±17 fig mL-1 . The compound accumulated extensively in kidney tissue, ratios up to 175 times the perfusate concentration were reached. Accumulation data were best analysed by a two-site model similar to the model used to describe renal excretion. Calculated parameters were theoretical maximum capacity of the high affinity site (Rm,h) = 26 ± 23 f i g g~\ affinity constant for renal accumulation at the high affinity site (KaiH ) = 0*2±04 ¿¿gmL" 1, theoretical maximum capacity of the low affinity site (RM<) = 1640± 1100 jug g and affinity constant for renal accumulation at the low affinity site (K a ,l) = 60± 58 fig mL-1 .TThe very high accumulation in kidney tissue could be explained by active tubular uptake, mediated by the secretory mechanisms involved, and dependent on the amount of free drug in the perfusate. This study shows that anionic drugs, subject to active secretion, may reach high concentrations in tubular cells even at low plasma concentrations.

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Section: Renal Excretion and Accumulationcontrasting

confidence: 99%

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confidence: 99%

Renal Excretion and Accumulation Kinetics of 2-Methylbenzoylglycine in the Isolated Perfused Rat Kidney

Masereeuw

Moons

Rüssel

1996

Journal of Pharmacy and Pharmacology

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“…Thus, beside a carrier role, it has been proposed that albumin could also facilitate the cellular uptake and renal secretion of organic anions (Besseghir et al, 1989). Furosemide is rapidly eliminated by renal extraction, via the tubular organic anion system transport, and by biotransformation to approximately the same extent (Hammarlund-Udenaes & Benet, 1989;Boles Ponto & Schoenwald, 1990a,b).…”

Section: Introductionmentioning

confidence: 99%

The influence of moderate hypoalbuminaemia on the renal metabolism and dynamics of furosemide in the rabbit

Pichette

Geadah

Souich

1996

British J Pharmacology

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1 The present study aimed to investigate the influence of hypoalbuminaemia on the pharmacokinetics and pharmacodynamics of furosemide. Hypoalbuminaemia was produced by repeated plasmapheresis, to attain plasma albumin concentrations of 21.6+0.9 g 1', compared with 33.0+0.6 g 1' in controls (P<0.001). The per cent of bound furosemide in hypoalbuminaemic rabbits (90.8+0.7%) was lower than that in control rabbits (97.4+0.5%, P<0.001). The kinetics of intravenous furosemide (2.5 mg kg-') were studied in control (n = 6) and hypoalbuminaemic rabbits (n = 6). 2 To assess the effect of hypoalbuminaemia on extrarenal clearance of furosemide, functional anephria was induced by ligating the renal pedicles of 12 rabbits, which were segregated in two groups, with and without hypoalbuminaemia. 3 In the control group, total, urinary and metabolic clearances of furosemide were 1.8 + 1.0, 5.0 + 0.4 and 6.8 + 0.6 ml min-' kg-', respectively. Compared with control rabbits, in hypoalbuminaemic rabbits, total clearance of furosemide increased by 40% (P<0.001), result of the enhancement of furosemide metabolic clearance (Clm) from 5 to 10 ml min-' kg-' (P<0.01). In hypoalbuminaemic rabbits, urinary excretion of furosemide was reduced by 26% (2451 + 115 vs 1818 + 134 pg h-', P<0.01). In anephric rabbits, furosemide total clearance was 1.77+0.12 ml min-' kg-', value not affected by hypoalbuminaemia, confirming that the increase in Clm induced by hypoalbuminaemia occurs in the kidneys. 4 Compared with controls, in hypoalbuminaemic rabbits, the rate of urinary excretion (142+9 vs 74+8 ml h-', P<0.001) and the rate of excretion of sodium (18.6+0.9 vs 9.9+0.9 mmol h-', P<0.001) were very much reduced. However, the dose-response curves were not different. 5 In conclusion, hypoalbuminaemia is associated with an increase in renal metabolic clearance of furosemide, possibly because of the increase in furosemide unbound concentration, and a decrease in the diuretic/natriuretic effect of furosemide, secondary to a reduction in furosemide tubular secretion. Thus, albumin facilitates the renal secretion of organic anions but not their metabolism.

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“…The low free concentrations available for diffusion through the capillary endothelium would require a robust transporter to maintain a maximal gradient for diffusion throughout the length of the peritubular capillary. The success of this postulated mechanism for stripping bound ligands from albumin has been demonstrated in vitro as well as in the isolated perfused rat kidney (6). In humans and whole animals, tubular secretion of phenol red results in Ͼ80% extraction during a single pass through the kidneys despite 90% binding to serum albumin (4).…”

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confidence: 99%