Serum protein binding of itraconazole and fluconazole in patients with diabetes mellitus

Abstract

The protein binding of itraconazole and fluconazole in the serum of patients with insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetes mellitus was investigated in vitro. The unbound percentage of itraconazole in patients with IDDM and NIDDM was significantly higher than that in healthy volunteers. In contrast, there were no significant differences in fluconazole protein binding. A negative correlation was established between itraconazole protein binding and albumin concentration, and a positive correlation with free fatty acid concentration. The existence of a larger percentage of unbound itraconazole in diabetes patients could imply a change in drug disposition and an alteration in the effect of the drug. This should be taken into consideration in long duration treatment, especially in view of the non-linear kinetics of itraconazole.

Has the era of individualised medicine arrived for antifungals? A review of antifungal pharmacogenomics

“…At least in the case of itraconazole, this results in increased levels of unbound drug. 5 Structural variation in plasma proteins, such as is seen in the genetic variants of albumin, 6,7 may affect substrate binding, 8 but no relevant data are yet available as to whether this affects antifungal drugs.…”

Human Pharmacogenomic Variations and Their Implications for Antifungal Efficacy

“…However, A 1 -acid glycoprotein and lipoproteins can also contribute to drug binding (20,30,174,218). To a lesser degree, antifungal agents can bind to hemoglobin A1 and free fatty acids (10,225), as well as on red blood cells (171). For instance, extensive uptake by red blood cells was noted for micafungin (63), while coadministration of caspofungin with tacrolimus reduces whole-blood tacrolimus levels by 20%, possibly due to decreased red blood cell binding of the latter (65).…”

“…Although substantial variation in plasma proteins can occur in pathological situations, such as diabetes (106), levels of proteins can vary up to 10% among healthy individuals (136). Interindividual variation (5%) in drug-protein binding rates for itraconazole and fluconazole has been observed, with a significant association between the binding of drugs and serum protein levels (8). Plasma protein binding of terbinafine had a major effect on brain uptake in rats, varying from 6% to 45% in the presence of plasma, albumin, and very low-(VLDL) and low-density lipoproteins (LDL), A 1 -acid glycoprotein, and high-density lipoproteins (HDL) (174).…”

“…Of the common antifungal agents, ketoconazole (177), itraconazole (8), amphotericin B (20,109), caspofungin (244), and terbinafine (174,218) bind to albumin, while fluconazole does not (9,10). Site II is involved in the binding of both amphotericin B and nystatin, while amphotericin B also binds to site I and nystatin binds to the fatty acid binding sites in albumin (216).…”

“…Although the binding of ketoconazole (177) and itraconazole (10) might not be directly related to circulating AAG levels, an increase in binding of fluconazole is associated with higher levels of AAG (8); some have interpreted this to mean that fluconazole has a higher affinity for AAG than for albumin (9). AAG has been found to contribute to amphotericin B (20) and terbinafine (174) binding.…”