Pharmacological profile and toxicity of fluorescein-labelled sinistrin, a novel marker for GFR measurements

Abstract

There is an evident and growing medical need for an accurate determination of kidney function for a broad spectrum of indications. The glomerular filtration rate (GFR) is the most accepted indicator of renal function. Due to difficulties in performing the test, GFR is currently determined rarely in clinical practice. A procedure for such GFR determination has to be safe, accurate and easy to handle. By using the new compound fluorescein isothiocyanate-sinistrin (FS) these requirements are met. The pharmacological profile and tolerability of FS, selected from among various newly synthesized, labelled compounds intended for use as GFR markers, was characterized in male Sprague-Dawley rats following i.v. application. Using the newly described fluorometric method, FS can be determined much more easily in serum and urine than with the established enzymatic method. After i.v. dosing, FS concentrations in serum declined rapidly in various experimental groups to a comparable extent (t (1/2), mean+/-SD: 22.4+/-8.3 to 26.2+/-5.4 min). Its increase after unilateral nephrectomy reflects the loss of filtration capacity. Comparable concentration-time curves of FS in serum measured fluorometrically and enzymatically suggest no relevant alteration of pharmacokinetic behaviour by the labelling. This notion is supported by the high urinary excretion rate and absence of biliary excretion. The higher sensitivity of the fluorometric method suggests a dose of FS of 100 mg in humans compared with 5 g of sinistrin or inulin. FS was well tolerated after single and multiple applications. On the basis of these results, the kinetics of FS are comparable with the gold standard inulin or sinistrin, but FS is superior in handling. Providing the data can be transferred from rat to human, determination of GFR using the new method should result in an improvement of acceptance by both physicians and patients.

Transcutaneous assessment of renal function in conscious rats with a device for measuring FITC-sinistrin disappearance curves

“…7,16,17 After a baseline period, where the system detects a constant background signal, FITCsinistrin (63 mg per 100 g body weight (b.w.)) was injected via a catheter into the left femoral vein.…”

“…Moreover, the fructan moiety of the FITC-sinistrin was determined enzymatically in plasma samples as a gold standard technique of GFR measurement, as published before. 7,16,17,19 From the plasma samples the rate constant and elimination half-life were calculated using an established one compartment model ( Figure 2b). 7,16,17 In addition, a two compartment model was fitted to the transcutaneous data for half-life determination (see Supplementary Data online).…”

“…15 The theoretical background of this fact is beyond the scope of this Technical Note, the interested reader is referred to recent literature. 15 In this Technical Note, we focus on a novel device for the transcutaneous measurement of the elimination kinetics of the fluorescent-labeled exogenous GFR marker fluorescein isothiocyanate (FITC)-sinistrin 7,16,17 in freely moving rats.…”

Bias and precision of estimated glomerular filtration rate in children

“…By labelling inulin with FITC [27,28], it was possible to determine GFR by measuring the dye label. The problem of FITC inulin, however, is its poor solubility, which has been overcome by using sinistrin instead of inulin [29]. Recently, Rabito et al [30] published a new GFR marker, which can be determined transcutaneously: Carbostyril124-DTPA-Eu.…”

Simplified Method to Measure Glomerular Filtration Rate by Iohexol Plasma Clearance in Conscious Rats

“…Alternative strategies using fluorescent markers have been adopted in experimental animals [26,27,28]. Some of these fluorescent markers are chelates of europium with DTPA [29], but they may have some drawbacks due to their nephrotoxicity.…”