Plasma and Tissue Protein Binding of Drugs in Pharmacokinetics

Disclosed are methods and compositions for monitonng, diagnosis, prognosis, and determination of treatment regimens in subjects suffering from or suspected of having a renal injury The methods use assays that detect one or more markers selected from the group consisting of Cytoplasmic aspartate aminotransferase, soluble Tumor necrosis factor receptor superfamily member 5, soluble CD40 Ligand, soluble C-X-C Motif chemokine 16, SIOO-AI2, Eotaxin, soluble E-selectin, Fibronectin, Granulocyte colony-stimulating factor, Granulocyte-macrophage colony-stimulating factor, Heparin-binding growth factor 2, soluble Hepatocyte growth factor receptor, Interleukin-I receptor antagonist, Interleukin-I beta, lnterleukιn-10, lnterieukιn-15, lnterieukιn-3, Myeloperoxidase, Nidogen-I, soluble Oxidized low-density lipoprotein receptor I, Pappalysin-I, soluble P-selectin glycoprotein ligand I, Antileukoproteinase, soluble Kit ligand, Tissue inhibitor of metalloproteinaseI, Tissue inhibitor of metalloproteinase 2, soluble Tumor necrosis factor, soluble Vascular cell adhesion molecule I, and Vascular endothelial growth factor A.

Method and compositions for diagnosis and prognosis of renal injury and renal failure

Separation procedures used to reveal and follow drug-protein binding.

The extent and nature of furosemide (F) binding to human albumin (HA) and to the plasma of 6 children with nephrotic syndrome were studied by equilibrium dialysis at 37 degrees C and pH 7.4 with 14C-F. At a total concentration of 3.4 mug/ml (therapeutic range), the unbound fraction of F to 4 gm per 100 ml HA was 2.79 plus or minus 0.35. The degree of binding was relatively constant from 1.8 to 36 mug/ml of F concentration. The percentage of unbound F doubled when total concentration of the drug was increased more than 130 times (1.8 to 245 mug/ml). F has two classes of binding sites (n1 = 1.42, k1 = 5.07 times 10-4 M-minus 1; n2 = 3.4, k2 = 1.58 times 10-4 M-minus 1); interaction with HA involves hydrophobic, ionic, and hydrogen forces. Acetylsalicylic acid (ASA), acetazolamide, diazoxide, phenylbutazone, sulfisoxazole (S), and tolbutamide (T) decreased F binding. Combinations of ASA, S, and T exerted a strong additive displacing effect. The binding of the F metabolite (4-chloro-5-sulfamoylanthranilic acid, CSA) was studied at 1.3 and 2.6 mug/ml. The unbound fraction was 5 times that of F. CSA did not influence F binding. Studies with plasma of 7 healthy adults showed that albumin is the only plasma protein responsible for F binding. The plasma albumin concentration range of the children with nephrotic syndrome was 0.6 to 2.1 gm per 100 ml. There was some correlation between albumin concentration and binding of F (2.8 to 9.6% unbound); this corresponded with findings with HA. Albumin concentrations lower than 2 gm per 100 ml seemed to influence the extent of the unbound fraction of F considerably.

Furosemide binding to human albumin and plasma of nephrotic children.

Frusemide is an anthranilic acid derivative that is pharmacologically more potent than organomercurial agents in producing natriuresis and is effective when taken orally even in acid-base disorders or advanced renal failure. The bioavailability of commercially prepared tablets is comparable to an aqueous solution of frusemide. In healthy subjects the range of oral absorption is 60 to 69%. In patients with end-stage renal disease (ESRD), absorption is reduced to values between 43 and 46%. Food decreases the rate of absorption but does not affect bioavailability. Chronic phenytoin therapy, however, does reduce bioavailability to about the level of ESRD. Plasma protein binding in healthy subjects has been demonstrated to be between 91 and 99%. Frusemide is almost exclusively bound to albumin and it competes for binding sites with other acidic drugs. In patients with reduced plasma albumin concentration or azotaemia, frusemide binding is reduced. The mean apparent volume of distribution in the steady-state ranges from 0.07 to 0.18L/kg body weight in healthy adults. It may be modestly increased in adults with cardiac failure, but is very large in neonates with fluid overload. After intravenous injection, intact frusemide is the major urinary product in the first 4 hours. After this time, frusemide glucuronide and the free amine metabolite are also found. In healthy subjects, between 6 and 18% of an intravenous dose is found in the faeces. However, in renal failure, this is increased to 60% of the injected dose. Although apparently secreted by proximal portions of the nephron, frusemide has its principal action on the luminal surface of the ascending limb of Henle’s loop. In this segment it exerts an inhibitory action on active chloride, thus producing a saluresis of both sodium and chloride. Probenecid substantially reduces the renal secretion of frusemide and the plasma clearance, and prolongs the half-life of the drug without impairing its natriuretic effect. Frusemide plasma clearance is greater than the creatinine clearance except in ESRD where it tends to be about 50% of the measured value. Elimination half-lives of 19 to 100 minutes are reported in healthy subjects but may be 8 to 15 hours in ESRD. In patients with both hepatic and renal insufficiency, reported half-lives were 11 to 20 hours. In neonates elimination half-lives of 7 to 8 hours have been reported apparently due to very large distribution volumes as well as low renal and hepatic clearance. Although the natriuretic effect of frusemide is variable and apparently dependent on the state of sodium reabsorption at the site of drug action, it appears that the saluretic response is more closely correlated with the urinary concentration of frusemide than with the plasma level. If the salt and water balance is maintained, a sigmoid-shaped dose-response curve is observed. From a therapeutic viewpoint, the maximum response with the least amount of drug would occur if the urinary excretion of frusemide were on the ‘steep’ portion of the curve. This concept has been applied in several clinical studies and probably explains the greater natriuresis seen when a divided oral dose regimen is given or small continuous infusions have been used.

Clinical Pharmacokinetics of Frusemide

We describe a modification of the fluorometric method of Haussler and Hajdu [ Arzneim. Forsch. 14, 704 and 709 (1964)] for assay of furosemide in either serum or urine. A 1-ml sample, acidified to pH 2, is extracted with 5 ml of diethyl ether; 4 ml of the ether is back-extracted into 1 ml of phosphate buffer (pH 7.0, 0.1 mol/liter), and finally acidified with 1 ml of dilute HCl (0.6 mol/liter). A procedure for estimating blanks in urine was derived to correct for dilution caused by diuresis. Internal standards are used, and the "effective" extraction ratio is used to correct for the effects of quenching and extraction differences. In equilibrium, 93% of the drug is bound to serum proteins; 65% is tightly bound. Erythrocytes contain less than 5% of the drug. Quantum yield of fluorescence at pH 1 is 0.0496 for furosemide and is 0.0163 for 4-chloro-5-sulfamoylanthranilic acid. Furosemide fluorescence diminishes with increasing pH, while that of 4-chloro-5-sulfamoylanthranilic acid (a degradation product) increases.

Furosemide Concentrations in Serum and Urine, and Its Binding by Serum Proteins as Measured Fluorometrically

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Furosemide Concentrations in Serum and Urine, and Its Binding by Serum Proteins as Measured Fluorometrically