Multidrug resistance protein 2 (MRP2) is an ATP-dependent transporter of anionic drugs and conjugates. It functions as an efflux pump in the apical membranes of liver and kidney cells, but its membrane localization in small intestine has not yet been defined. The present study demonstrates exclusive localization of Mrp2 to the brush-border (apical) membrane of villi, decreasing in intensity from the villus tip to the crypts.
View Article and Find Full Text PDFThe anionic drug probenecid has been traditionally used as an inhibitor of renal organic anion transport. More recently the drug was found to inhibit organic cation transport as well, and it is used to retain intracellularly loaded fluorophores. In these investigations it is implicitly assumed that probenecid performs its activity through competition for transport.
View Article and Find Full Text PDFSulphonylurea drugs have been shown to protect against hypoxic damage in isolated proximal tubules of the kidney. In the present study we investigated whether these drugs can protect against hypoxic damage in a whole kidney preparation. Tolbutamide (200 microM) and glibenclamide (10 microM) were applied to the isolated perfused rat kidney prior to changing the gassing from oxygen to nitrogen for 30 min.
View Article and Find Full Text PDFRenal organic anion transport systems play an important role in the elimination of drugs, toxic compounds, and their metabolites, many of which are potentially harmful to the body. The renal proximal tubule is the primary site of carrier-mediated transport from blood to urine of a wide variety of anionic substrates. Recent studies have shown that organic anion secretion in renal proximal tubule is mediated by distinct sodium-dependent and sodium-independent transport systems.
View Article and Find Full Text PDFIn many Dutch hospitals gastric lavage leaving charcoal and a laxative is the treatment of choice after autointoxication. Gastric lavage is not without risks. No difference has been demonstrated in efficacy and safety of gastric lavage combined with administration of activated charcoal on the one hand and just administration of activated charcoal on the other.
View Article and Find Full Text PDFThe fluorescent organic anion fluorescein (FL) accumulates in proximal tubular cells of the kidney during renal secretion. In freshly isolated and permeabilized proximal tubular cells, the uptake was reduced but still sensitive to probenecid, suggesting a concentrative mechanism that is associated with intracellular compartments. Previous studies have shown that one of these compartments may be mitochondrial.
View Article and Find Full Text PDFIn the kidney, endothelins (ETs) are important regulators of blood flow, glomerular hemodynamics, and sodium and water homeostasis. They have been implicated in the pathophysiology of acute ischemic renal failure, nephrotoxicity by cyclosporine, cisplatin and radiocontrast agents, and vascular rejection of kidney transplants. Here, we used intact killifish renal proximal tubules, fluorescent substrates for Mrp2 (fluorescein-methotrexate, FL-MTX) and P-glycoprotein (a fluorescent CSA derivative, NBD-CSA), and confocal microscopy to reveal a new role for renal ET: regulation of ATP-driven drug transport in proximal tubule.
View Article and Find Full Text PDFThe present study examined how the multidrug resistance protein (MRP) 2, which is an ATP-dependent anionic conjugate transporter, also mediates transport of the chemotherapeutic cationic drug vinblastine (VBL). We show that ATP-dependent [(3)H]VBL (0.2 microM) uptake into membrane vesicles from Sf9 cells infected with a baculovirus encoding rabbit Mrp2 (Sf9-Mrp2) was similar to vesicles from mock-infected Sf9 cells (Sf9-mock) but could be stimulated by reduced glutathione (GSH) with a half-maximum stimulation of 1.
View Article and Find Full Text PDFJ Cardiovasc Pharmacol
September 1999
Besides an evident diuretic effect, amiloride has been shown to exert direct vasoactivity in various animal experiments, whereas human data on this issue are lacking. Inhibition of Na+/H+ exchange, alpha-adrenergic blockade, and sodium and calcium channel antagonism have been proposed as possible mechanisms of this action. Although the role of Na+/H+ exchange in vascular-tone modulation is not completely clear, various vasoconstrictive agents (e.
View Article and Find Full Text PDFRecent studies show that organic anion secretion in renal proximal tubule is mediated by distinct sodium-dependent and sodium-independent transport systems. Here we investigated the possibility that organic anions entering the cells on one system can exit into the lumen on a transporter associated with the other system. In isolated rat kidneys perfused with 10 microM lucifer yellow (LY, a fluorescent organic anion) plus 100 micrograms/ml inulin, the LY-to-inulin clearance ratio averaged 1.
View Article and Find Full Text PDFHippurates tend to accumulate within proximal tubule cells during renal secretion. High intracellular concentrations can alter proximal tubular function or lead to tubular toxicity. In this study we examined the renal disposition of the hippurate 4-methylbenzoylglycine, a compound known for its high renal intrinsic clearance in-vivo.
View Article and Find Full Text PDF-Hydrochlorothiazide and indapamide are thought to exert their hypotensive efficacy through a combined vasodilator and diuretic effect, but in vivo evidence for a direct vascular effect is lacking. The presence and mechanism of a direct vascular action of hydrochlorothiazide in vivo in humans were examined and compared with those of the thiazide-like drug indapamide. Forearm vasodilator responses to infusion of placebo and increasing doses of hydrochlorothiazide (8, 25, and 75 microg.
View Article and Find Full Text PDFIn this review we summarized literature data on the mechanisms of human placental drug transport studied in the isolated perfused placental cotyledon, placental membrane vesicles or trophoblastic cell cultures. Overall human placental drug transport rarely exceeds the transfer of flow-dependent and membrane-limited marker compounds. Interestingly, relatively often placental drug transfer appeared to be much smaller, indicating impaired trans-placental transport, depending on the physico-chemical characteristics of the drug or placental factors such as tissue binding or metabolism.
View Article and Find Full Text PDFJ Chromatogr B Biomed Sci Appl
June 1998
A new method is described for the solid-phase extraction of 18beta-glycyrrhetinic acid from plasma or serum, with subsequent analysis by HPLC. New aspects of the method include the use of commercially available 18alpha-glycyrrhetinic acid as the internal standard and the use of a Bond Elut C2 (ethyl) extraction column, to avoid the need to use large volumes of organic solvent to elute the isolates from the columns. Separation was achieved on a Shandon Hypersil BDS C18 analytical column, with a mobile phase consisting of acetonitrile-0.
View Article and Find Full Text PDFThe multidrug resistance-associated protein Mrp2 is expressed in liver, kidney, and small intestine and mediates ATP-dependent transport of conjugated organic anions across the apical membrane of epithelial cells. We recently cloned a rabbit cDNA encoding a protein that on basis of highest amino acid homology and tissue distribution was considered to be the rabbit homolog of rat Mrp2. To investigate whether rabbit Mrp2 mediates ATP-dependent transport similar to rat Mrp2, we expressed rabbit Mrp2 in Spodoptera frugiperda (Sf9) cells using recombinant baculovirus.
View Article and Find Full Text PDFRanitidine renal clearance was investigated in the beagle dog with or without concomitant infusion of cimetidine or probenecid. Ranitidine was excreted mainly by renal tubular secretion. Plasma clearance was reduced by probenecid from 198 +/- 47 to 119 +/- 41 mL min-1 (mean +/- SD.
View Article and Find Full Text PDFSevere congestive heart failure (CHF) is often characterised by fluid retention. A (chronic) state of overhydration has a negative influence on both the quality of life and prognosis of these patients. Therefore, the use of diuretics remains a cornerstone in the treatment of heart failure.
View Article and Find Full Text PDFAims: To investigate the nasal absorption of hydroxocobalamin in 10 healthy elderly adults.
Methods: In a cross-over study, blood samples were collected before administration of the drug and after 10, 20, 30, 40, 60, 120, 180 and 240 min. The plasma cobalamin concentration was determined by competitive radioisotope binding technique.
Background: In humans, hemodynamic changes observed within minutes after systemic administration of furosemide are often referred to as direct vasoactivity. However, these immediate changes do not per se imply a direct vascular effect. We examined the genuine direct vascular effects of furosemide on the human forearm vascular bed and dorsal hand vein.
View Article and Find Full Text PDFRhodamine 123 has been shown to be a substrate for P-glycoprotein in multidrug resistant cells. In the present investigation the disposition of rhodamine 123 was studied in the isolated perfused rat kidney. After exposing the kidneys to perfusate concentrations ranging from 10 to 1000 ng/ml, the renal clearance was 4-1 times the clearance by glomerular filtration, respectively, indicating active and saturable secretion of rhodamine 123.
View Article and Find Full Text PDFAn important elimination route of the histamine H2 antagonist famotidine is active tubular secretion via the renal organic cation transport system. To characterize the excretion kinetics of famotidine in-vivo, the relationship between plasma concentration and urinary excretion rate was investigated in the beagle dog over a wide concentration range. The maximum transport capacity and the apparent Michaelis-Menten constant of tubular secretion were estimated.
View Article and Find Full Text PDFThe role of tubular accumulation in renal disposition and diuretic efficacy of hydrochlorothiazide was studied in the isolated perfused rat kidney. Hydrochlorothiazide resulted in a dose-dependent increase in the fractional excretion of sodium, chloride and potassium, and in urinary flow and pH. Renal clearance of the drug was low as a result of a low extraction ratio and extensive nonionic back-diffusion.
View Article and Find Full Text PDFAlthough it is generally believed that the beneficial effect of loop diuretics is the result of a rapid increase in diuresis, substantial evidence, from a large number of in vitro and in vivo experiments, has accumulated showing that administration of furosemide causes direct vascular effects, which probably contribute to its acute clinical effects. Several mechanisms are involved in the vascular response to loop diuretics. The role of the renin-angiotensin-adolsterone axis, prostaglandins and the direct vascular effects of loop diuretics on both the arterial and venous parts of the vasculature are discussed.
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