Summary
Chronic hyperglycaemia results in glycation of serum albumin and might affect the binding of drugs. The aim of the present study was to compare, using an equilibrium dialysis method, the protein binding of therapeutic concentrations digitoxin, valproate and phenytoin in sera from 70 insulin-dependent diabetics and 25 controls. Drug concentrations were measured by fluorescence immunopolarisation. Glycated albumin was measured by laser nephelometry after affinity chromatography.
In sera from diabetics, protein binding of digitoxin (88.8 versus 89.9%) was unchanged; the protein binding of valproate (75.2 versus 80.7%) and phenytoin (67.9 versus 75.3%) was significantly decreased, but with no correlation with the concentration of glycated albumin.
We conclude that the difference in protein binding between diabetic and control sera is due to glucose-independent modification of albumin in diabetics.
References
Buhn HF, Gabbay KH, Gallop PM (1978) The glycosylation of hemoglobin: relevance to diabetes mellitus. Science 200: 21–27
Brownlee M, Vlassara H, Cerami A (1980) Measurement of glycosylated amino acids and peptides from urine of diabetic patients using affinity chromatography. Diabetes 29: 1044–1047
Ruiz-Cabello F, Erill S (1984) Abnormal serum protein binding of acidic drugs in diabetes mellitus. Clin Pharmacol Ther 36: 691–695
Tsuchiya S, Sakurai T, Sekiguschi SI (1984) Nonenzymatic glucosylation of human serum albumin and its influence on binding capacity of sulfonlylureas. Biochem Pharmacol 33: 2967–2971
Gatti G, Crema F, Attardo-Parinello G, Fratino P, Aguzzi F, Perucca E (1987) Serum protein binding of phenytoin and valproic acid in insulin-dependent diabetes mellitus. Therap Drug Monit 9: 389–391
Kemp S, Kearns GL, Turley CP (1987) Alteration of phenytoin binding by glycosylation of albumin in IDDM. Diabetes 36: 505–509
MacNamara PJ, Blouin RA, Brazzell RK (1988) The protein binding of phenytoin, propranolol, diazepam and AL 01576 (an aldose-reductase inhibitor) in human and rat diabetic serum. Pharm Res 5: 261–265
Kearns GL, Kemp SF, Turley CP, Nelson DL (1988) Protein binding of phenytoin and lidocaine in pediatric patients with type I diabetes mellitus. Dev Pharmacol Therap 11: 14–23
Kradjan WA, Kobayashi KA, Bauer LA, Horn JR, Opheim KE, Wood FJ (1989) Glipizide pharmacokinetics: effects of age, diabetes and multiple dosing. J Clin Pharmacol 29: 1121–1127
Grainger-Rousseau TJ, McElnay JC, Collier PS (1989) The influence of disease on plasma protein binding of drugs. Int J Pharm 54: 1–13
Kostic BAP, Olsen KM, Kearns GL, Kemp SF (1990) Effect of glycated albumin on phenytoin binding in elderly patients with type II diabetes mellitus. Pharmacotherapy 10: 362–365
Kurz H, Trunk H, Weitz B (1977) Evaluation of methods to determine protein-binding of drugs: Equilibrium dialysis, ultrafiltration, ultracentrifugation, gel filtration. Drug Res 27: 1373–1380
Sjöholm I, Ekman B, Kober A, Ljunstedt-Pahlman I, Jeiving B, Sjodin T (1979) The specificity of three binding sites as studied with albumin immobilized in microparticules. Mol Pharmacol 16: 767–777
Cramer JA, Mattson RH (1979) Valproic acid: in vitro plasma protein binding and interaction with phenytoin. Ther Drug Monit 9: 105–116
Urien S, Albengres E, Tillement JP (1981) Serum protein binding of valproic acid in healthy subjects and in patients with liver disease. Int J Clin Pharmacol Ther Toxicol 19: 319–325
Garlick RL, Mazer JS (1983) The principle site of nonenzymatic glycation of human serum albumin in vivo. J Biol Chem 258: 6142–6146
Shaklai N, Garlick RL, Bunn HF (1984) Nonenzymatic glycosylation of human serum albumin alters its conformation and fonction. J Biol Chem 259: 3812–3817
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Doucet, J., Fresel, J., Hue, G. et al. Protein binding of digitoxin, valproate and phenytoin in sera from diabetics. Eur J Clin Pharmacol 45, 577–579 (1993). https://doi.org/10.1007/BF00315318
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DOI: https://doi.org/10.1007/BF00315318