The serum protein binding of itraconazole and fluconazole, new triazole antifungal agents, has been investigated in vitro in the serum of healthy volunteers and in patients with chronic renal failure (predialysis). Protein binding was determined by ultrafiltration. Concentrations of both alpha 1-acid glycoprotein (AAG) and albumin were measured in all serum samples. The protein binding of itraconazole showed no significant changes in patients with chronic renal failure when compared to healthy volunteers (96.64 +/- 0.99% vs. 96.85 +/- 0.33%). In contrast, fluconazole protein binding was significantly increased in the same patients (22.91 +/- 6.15% vs. 12.51 +/- 2.37%; p < 0.001). In addition, whereas albumin levels in the latter patients were significantly decreased (p < 0.001), their AAG levels were found to be significantly elevated with respect to control subjects (p < 0.001). While no correlation was established between itraconazole protein binding and albumin or AAG concentrations, a significant correlation was found between fluconazole protein binding and AAG levels (r = 0.72; p < 0.001). Fluconazole protein binding was found to be independent of albumin concentrations. In vitro carbamylation of serum protein with potassium cyanate caused no changes in the protein binding of fluconazole or itraconazole. We conclude that the binding of itraconazole by serum proteins is not altered in diseases involving changes of AAG or albumin concentrations. However, fluconazole protein binding may be altered in disease states associated with increased AAG concentrations.