BackgroundVoriconazole concentrations display a large variability, which cannot completely be explained by known factors. We investigated the relationships of voriconazole concentration with patient-specific variables and concomitant medication to identify clinical factors affecting voriconazole clearance.MethodsA retrospective chart review of voriconazole trough concentration, laboratory data, and concomitant medication in patients was performed. The concentration/dose ratio (C/D-ratio) was assessed as a surrogate marker of total clearance by dividing voriconazole concentration by daily dose per kg of body weight.ResultsA total of 77 samples from 63 patients were obtained. In multiple linear regression analysis, increased C-reactive protein (CRP) level (p < 0.05) and decreased albumin (Alb) level (p < 0.05) were associated with significantly increased C/D-ratio of voriconazole, and coadministration with a glucocorticoid was associated with significantly (p < 0.05) decreased C/D-ratio of voriconazole (adjusted r2 = 0.31). Regarding CRP and Alb, receiver operating characteristic curve analysis indicated that increased CRP level and decreased Alb level were significant predictors of toxic trough concentration of voriconazole. For CRP, area under the curve (AUC) and cutoff value were 0.71 (95 % confidence interval (CI), 0.57–0.86, p < 0.01) and 4.7 mg/dl, respectively. For Alb, AUC and cutoff value were 0.68 (95 % CI, 0.53–0.82, p < 0.05) and 2.7 g/dl, respectively. A significant difference was seen in voriconazole trough concentration between patients with hepatotoxicity and those without (5.69 μg/ml vs 3.0 μg/ml, p < 0.001).ConclusionCoadministration of glucocorticoid and inflammation, reflected by elevated CRP level and hypoalbuminemia, are associated with voriconazole clearance. We propose that early measurement of voriconazole concentration before the plateau phase will lead to avoidance of a toxic voriconazole level in patients with elevated CRP level and hypoalbuminemia, although further studies are needed to confirm our findings.

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The NADP(H)-linked oxidoreductase activity of a major isozyme of human liver 3 alpha-hydroxysteroid dehydrogenase was activated 5-, 4-, and 2-fold by D-thyroxine (T(4)), L-T(4) and DL-3,3', 5'-triiodothyronine (reverse T(3)), respectively. Kinetic analysis of the activation indicated that D-T(4), L-T(4), and reverse T(3) are non-essential activators, showing binding constants of 1.5, 1.1, and 3.6 microM, respectively. Comparison of the effects of the T(4) analogs on the activities of the mutant enzymes suggests that the binding site is composed of at least Lys-270, Arg-276, and the C-terminal loop of the enzyme. L-T(3), DL-thyronine, and D-tyrosine had no effect on the enzyme, but 3,5,3',5'-tetra- and 3,5, 3'-tri-iodo thyropropionic acids were potent competitive inhibitors with K(i) values of 42 and 60 nM, respectively, with respect to the substrate. The inhibition constant was lowered upon the activation of the enzyme by D-T(4), and the inhibition by the deamino derivatives of T(4) and T(3) disappeared upon modification of the C-terminal loop of the enzyme, but not upon replacement of Lys-270 or Arg-276 with Met. These results indicate that, depending on their structures, the T(4) analogs bind differently to two distinct sites at the active center of the enzyme to produce stimulatory and inhibitory effects.

The influence of pharmacist-supported insulin therapy on the safety and efficacy of blood glucose management in steroid therapy for hematologic malignancies complicated by diabetes in collaborative drug therapy management was examined. At the same time, an insulin dose-predicting factor required for blood glucose control was investigated. Changes in the blood glucose level after steroid administration were significantly decreased on medication support by a pharmacist compared to those in blood glucose control performed by a physician alone: the median (range) blood glucose level before breakfast, 138.6 (99.00 -189.0) mg/dL vs 156.4 (111.2 -204.6) mg/dL (P = 0.13); before lunch, 198.5 (128.7 -307.0) mg/dL vs 240.9 (157.7 -410.5) mg/dL (P < 0.01); before supper, 232.9 (161.7 -329.8) mg/dL vs 311.5 (157.4 -387.9) mg/dL (P < 0.01); before sleep, 247.5 (164.9 -338.7) mg/dL vs 293.3 (174.7 -345.9) mg/dL (P < 0.01), respectively. An index of daily glycemia excursions, Schlichtkrull M120 value, was also significantly decreased: 30.27 (5.96 -66.04) vs 58.63 (9.21 -93.68) (P < 0.001), respectively. The insulin dose was inversely correlated with the prednisolone dose (correlation coefficient: -0.511. P = 0.021), but no correlation with any other factor (dexamethasone dose, age, body mass index, and HbA1c (JDS)) was noted. The findings suggest that meticulous dose control in consideration of a patient's insulin sensitivity is essential for blood glucose control using insulin in steroid therapy, and cooperation between pharmacists and physicians facilitates precise blood glucose control, leading to safe and effective insulin therapy.

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