A Specific Radioimmunoassay for Estrone Sulfate in Plasma and Urine without Hydrolysis*

Wright, K.; Collins, Delwood C.; Musey, Paul I.; Preedy, J. R. K.

doi:10.1210/jcem-47-5-1092

Cited by 66 publications

(19 citation statements)

References 6 publications

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“…6A). This correlates well with ES in vivo data that report a low renal clearance (2.7 ml/min), indicative of no active secretion (Wright et al, 1978). Also for MTX, our results confirm both the in vivo and in vitro data from the literature; renal clearance of MTX (ϳ111 ml/min/m 2 ) exceeds GFR, indicating active secretion (Pauley et al, 2004), which has been linked to OAT-mediated transport (Uwai et al, 2004).…”

Section: Impact Of Albumin On the Renal Transport Of Organic Anions 351supporting

confidence: 91%

The Impact of Plasma Protein Binding on the Renal Transport of Organic Anions

Bow

Perry²,

Simon³

et al. 2006

The Journal of Pharmacology and Experimental Therapeutics

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Drugs and xenobiotics bind to plasma proteins with varying degrees of affinity, and the amount of binding has a direct effect on free drug concentration and subsequent pharmacokinetics. Multiple active and facilitative transport systems regulate the excretion of anionic compounds from the blood in excretory and barrier tissues. Assumptions are made about in vivo substrate affinity and route of elimination based on data from plasma protein-free in vitro assays, particularly following expression of cloned transporters. Ochratoxin A (OTA), a fungal mycotoxin, is a high-affinity substrate for several renal secretory organic anion transporters (OATs), and literature suggests that this elimination pathway is the route of entry leading to proximal tubule-targeted toxicity. However, OTA is known to bind to several plasma proteins with a high affinity, particularly serum albumin, which may impact elimination. In this study, we have systematically examined the handling of OTA and other organic anions, estrone sulfate (ES) and methotrexate (MTX), by OATs in the presence of serum albumin. Increasing concentrations of albumin markedly reduced uptake of OTA by both Xenopus laevis oocytes expressing OATs 1, 3, and 4 and organic anion-transporting polypeptide 1. For all transporters tested, virtually all mediated OTA uptake was eliminated by an albumin concentration equivalent to 10% of that present in the blood plasma. Thus, OTA uptake is dependent on the free substrate concentration and severely limited by binding to human serum albumin. MTX and ES uptake were likewise dependent on free concentration.The proximal tubule is the primary site for renal secretory elimination of drugs, toxins, and their metabolites from the body. In addition, the proximal tubule exhibits a very high metabolic demand since it mediates not only secretion of drugs and xenobiotics but also the reabsorption of 60 to 80% of the solute and water filtered by the glomerulus (Schnellmann, 2001). Thus, the proximal tubule is particularly susceptible to injury by drugs and toxins.Elimination of drugs, toxins, and their metabolites is handled by several facilitative and active epithelial transport proteins expressed in the proximal tubule. Since the advent of cloning and the extensive study of these transporters in vitro, the impact of plasma protein has generally been overlooked when predicting physiological roles of transporters in the renal elimination of drugs. Nevertheless, plasma proteins are abundant, and the potential for altered transporter efficacy is substantial. For example, serum albumin, a major transport/carrier plasma protein [4% (w/v)], makes up approximately 60% of total plasma protein (Peters, 1996;Gekle, 2005). Indeed, it has long been known that to predict the efficacy of a drug in vivo, it is critical to account for plasma protein binding because it will determine the availability of free drug, its half-life, and its subsequent renal elimination (Weiner et al., 1964).Certainly, the impact of binding will vary depending upon the af...

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Section: Impact Of Albumin On the Renal Transport Of Organic Anions 351supporting

confidence: 91%

The Impact of Plasma Protein Binding on the Renal Transport of Organic Anions

Bow

Perry²,

Simon³

et al. 2006

The Journal of Pharmacology and Experimental Therapeutics

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“…Therefore, another possibility is that OAT4 may contribute to avoid losing endogenous sulfated conjugates of steroid such as E 1 S and DHEAS, which are the reservoir of steroids in the blood circulation (29,30). These steroids are known to be tubular reabsorbed (31,32). In this case, OAT3 may be a basolateral efflux pathway for sulfate conjugates of steroids.…”

Section: Discussionmentioning

confidence: 99%

Human Organic Anion Transporter 4 Is a Renal Apical Organic Anion/Dicarboxylate Exchanger in the Proximal Tubules

et al. 2004

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Abstract. Human organic anion transporter OAT4 is expressed in the kidney and placenta and mediates high-affinity transport of estrone-3-sulfate (E 1 S). Because a previous study demonstrated no trans-stimulatory effects by E 1 S, the mode of organic anion transport via OAT4 remains still unclear. In the present study, we examined the driving force of OAT4 using mouse proximal tubular cells stably expressing OAT4 (S 2 OAT4). OAT4-mediated E 1 S uptake was inhibited by glutarate (GA) (IC 50 : 1.25 mM) and [14 C]GA uptake via S 2 OAT4 was significantly trans-stimulated by unlabeled GA (5 mM) (P<0.001).[3 H]E 1 S uptake via S 2 OAT4 was significantly trans-stimulated by preloaded GA (P<0.001) and its [ 14 C]GA efflux was significantly trans-stimulated by unlabeled E 1 S in the medium (P<0.05). In additon, both the uptake and efflux of [14 C]p-aminohippuric acid (PAH) and [14 C]GA via S 2 OAT4 were significantly trans-stimulated by unlabeled GA or PAH. The immunoreactivities of OAT4 were observed in the apical membrane of proximal tubules along with those of basolateral organic anion / dicarboxylate exchangers such as hOAT1 and hOAT3 in the same tubular population. These results indicate that OAT4 is an apical organic anion / dicarboxylate exchanger and mainly functions as an apical pathway for the reabsorption of some organic anions in renal proximal tubules driven by an outwardly directed dicarboxylate gradient.

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“…Previous methods of measuring oestrone sulphate have involved lengthy hydrolysis and extraction procedures (Palmer & Terqui, 1977). Even when direct measurements of oestrone sulphate have been achieved without prior hydrolysis there have still been up to three extraction steps (Wright, Collins, Musey & Preedy, 1978). However, Saba & Hattersley (1981) In the horse the material which is assayed as LH rises gradually from the time that behavioural oestrus is detected, reaches a peak on or after the day of ovulation and then gradually declines over the next 2-3 days (Whitmore, Wentworth & Ginther, 1973 ;Pattison et al, 1974 ;Noden et al, 1974Noden et al, , 1975.…”

Section: Animalsmentioning

confidence: 99%

Changes in oestrone sulphate concentrations in peripheral plasma of Pony mares associated with follicular growth, ovulation and early pregnancy

Makawiti¹,

Allen²,

Kilpatrick³

1983

Reproduction

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Summary. A simple and rapid ( < 2 h) immunoassay method has been developed based upon a novel separation technique called LIDIA (Ligand Differentiation Immunoassay), enabling direct estimation of the concentration of oestrone sulphate in ethanolic extracts of blood plasma. An antiserum raised against oestrone-3-glucuronyl\p=n-\BSA was used which showed a higher cross-reaction with the sulphate than the glucuronide metabolite. The assay had a sensitivity of 5\m=.\2 pg/tube and acceptable inter-( < 18%) and intra-(<8\m=.\5%)assay precision. Analysis of samples of peripheral venous plasma obtained daily from Pony mares showed that the mean concentration of oestrone sulphate started to rise from a baseline value ( < 300 pg/ml) at 6 days and reached a peak ( > 850 pg/ml) at 2 days before follicular rupture as determined by rectal palpation. Progesterone concentrations only started to rise above baseline ( < 0\m=.\5 ng/ml) on the day of ovulation and reached a peak 8 days later. Analysis of samples obtained during the first 30 days of pregnancy showed that there was no increase in oestrone sulphate at the time oestrus would have been expected had the mares not conceived.

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A Specific Radioimmunoassay for Estrone Sulfate in Plasma and Urine without Hydrolysis*

Cited by 66 publications

References 6 publications

The Impact of Plasma Protein Binding on the Renal Transport of Organic Anions

The Impact of Plasma Protein Binding on the Renal Transport of Organic Anions

Human Organic Anion Transporter 4 Is a Renal Apical Organic Anion/Dicarboxylate Exchanger in the Proximal Tubules

Changes in oestrone sulphate concentrations in peripheral plasma of Pony mares associated with follicular growth, ovulation and early pregnancy

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