Reflexiones terapéuticas / Therapeutic considerations

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

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.

Altered methadone analgesia due to changes in plasma protein binding: role of the route of administration.

1. The effect of experimental inflammation on methadone analgesia was evaluated in rats, by the tail-flick test, after single intravenous (0.35 mg/kg) and subcutaneous (3 mg/kg) doses. 2. After i.v. administration a significant decrease (P < 0.05) in the area under the methadone time-response curve was seen in rats with experimental inflammation, when compared with control. However, no differences in the analgesic response to methadone were detected between control rats and rats with inflammation when the drug was administered by s.c. injection. 3. Plasma mucoprotein levels were significantly increased (P < 0.001) and methadone free fraction was significantly decreased in rats with inflammation (P < 0.05). In addition, after i.v. methadone a decrease in brain uptake in rats with inflammation was detected. A significant correlation between brain uptake index and plasma free fraction was also observed. 4. These results suggest that a decreased immediate response to i.v. methadone may occur in circumstances in which there is an increase in alpha 1 acid glycoprotein, but that this is not likely to be observed when the absorption is not instantaneous.

Protein binding of itraconazole and fluconazole in patients with cancer.

The serum protein binding of itraconazole and fluconazole, new azole antifungal agents, has been investigated in vitro, in serum from healthy volunteers and from patients with cancer. Protein binding was determined by ultrafiltration. Concentrations of both alpha 1-acid glycoprotein (AAG) and albumin (HSA) were measured in all serum samples. The serum protein binding of itraconazole was reduced in patients (96.02 +/- 1.41% vs 97.25 +/- 0.54%; p < 0.01) with respect to healthy volunteers. In contrast, fluconazole protein binding was increased in the same group of patients (22.96 +/- 3.60% vs 13.30 +/- 2.58%; p < 0.01). HSA levels in cancer patients were significantly decreased (p < 0.01) and AAG levels were found to be significantly elevated in patients with respect to control subjects (p < 0.05). A significant linear relationship between the bound/unbound concentration ratio of itraconazole and HSA (r2 = 0.3340; p < 0.01) was found. Similarly, a significant relation was established between the bound/unbound concentration ratio of fluconazole and AAG levels (r2 = 0.2235; p < 0.05). Thus, a weak association between the binding of these drugs and serum protein levels has been observed. It is concluded that both antifungal drugs show different protein binding behaviour in cancer patients.

Protein binding of itraconazole and fluconazole in patients with chronic renal failure.

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.

Effect of halothane anesthesia and trifluoroacetic acid on protein binding of benzodiazepines.

The in vitro effect of the halothane metabolite, trifluoroacetic acid, on the protein binding of three different benzodiazepines (diazepam, lorazepam and midazolam) has been investigated. Furthermore, protein binding of these drugs was studied in serum from patients under the effect of halothane anesthesia (1-2.5%; 2.5 h). Trifluoroacetic acid, 4 mmol/l, displaced diazepam and midazolam from serum and produced a marked increase in the free percentage, but did not influence lorazepam binding. Moreover, 48 h after the end of halothane anesthesia, there were changes in protein binding of diazepam (3.9 +/- 0.3% at 48 h vs. 3.3 +/- 0.3% before halothane anesthesia; p less than 0.05). It can be concluded that halothane anesthesia (1-2.5%; 2.5 h) may temporarily potentiate the pharmacological effect of diazepam in the postoperative period following anesthetic procedures.

Decrease in penbutolol central response as a cause of changes in its serum protein binding.

Penbutolol is a beta-adrenoceptor antagonist that is extensively bound to alpha 1-acid glycoprotein (alpha 1-AGP), a protein that increases in inflammatory diseases thereby binding more drug in such conditions. Changes in serum binding can lead to modifications in the pharmacokinetics and pharmacodynamics of a drug, therefore, the central effect (as the anticonvulsant response) and brain uptake of penbutolol given intravenously to mice with experimental inflammation have been measured. A significant decrease of the central effect of penbutolol and its brain uptake was seen in diseased when compared with control animals (P less than 0.01). A parallel decrease in free fraction of penbutolol in diseased vs normal animals was detected. These results suggest that there is an increase in serum binding of basic drugs related to increments in alpha 1-AGP concentration, which reduces their central pharmacological effect.

Serum binding of ketoconazole in health and disease.

The plasma protein binding of ketoconazole, an oral antifungal agent of a weak basic nature, was measured after the addition of the drug (10 micrograms.ml-1) to serum from 35 healthy individuals, ten patients with chronic renal disease and seven patients with hepatic cirrhosis. The percentage of free ketoconazole was markedly increased in patients with chronic renal disease and in patients with hepatic cirrhosis, when it was compared with the group of healthy volunteers (7.33 +/- 0.11 in renal patients; 6.12 +/- 1.43 in hepatic patients compared with 2.93 +/- 0.12 in healthy individuals). The binding ratio of ketoconazole in health and disease was significantly related to plasma albumin concentration, but not to plasma alpha 1-acid glycoprotein (AAG) concentration. Moreover, ketoconazole binds to isolated human serum albumin in a greater proportion but does not bind to isolated AAG indicating that human serum albumin is the major binding protein for this drug in plasma.