Paradoxical early glucocorticoid induction of stem cell factor (SCF) expression in inflammatory conditions.

1. Stem cell factor (SCF) is a major growth factor for mast cells, promoting their differentiation and chemotaxis. Its expression is regulated by glucocorticoids in inflammatory conditions, showing an early increased protein expression, before the expected anti-inflammatory decrease (Da Silva et al., Br. J. Pharmacol. 2002:135,1634). 2. We here evaluated the early kinetic of SCF expression regulated by interleukin (IL)-1beta, budesonide and the combination of both in human lung fibroblasts in culture. 3. Budesonide potentiated the IL-1beta-enhanced expression of SCF mRNA (+103%) and protein (+98%) very shortly after treatment (at 30 min and 1 h, respectively). A gentle downregulation followed. This potentiating effect of budesonide was related to increased SCF mRNA stability and SCF gene transcription. 4. Deletion of a kappaB-like site that we identified in the first intron of the SCF gene, in a luciferase reporter system, abolished the potentiation by budesonide, as well as the effect of IL-1beta alone, as compared to the wild-type construction activity. 5. All budesonide-induced effects were glucocorticoid-receptor dependent, since they were reproduced by dexamethasone and blocked by RU486. 6. IL-1beta+budesonide did not affect the relative expression of the soluble and membrane-bound forms of SCF. 7. In conclusion, our results clearly show that glucocorticoids act very early to adversely increase the expression of SCF mRNA and protein in the inflammatory conditions created by IL-1beta, and that this effect involves increased mRNA stability and increased gene expression through activation of the NF-kappaB-like responsive element.

Reduction of the inhibitory effect of ketoconazole on budesonide pharmacokinetics by separation of their time of administration.

BACKGROUND: Budesonide is a glucocorticosteroid used in the treatment of, for example, inflammatory bowel diseases, with a recommended once-daily morning dosing regimen. Ketoconazole is a potent inhibitor of the cytochrome P450 3A (CYP3A) activities and known to inhibit the elimination of drugs metabolized by CYP3A, including budesonide. It is of therapeutic interest to know whether the influence of ketoconazole can be reduced by administration on an occasion different in time to CYP3A substrates. METHODS: Eight healthy men completed this randomized, open crossover study that comprised three different periods. In period 1, a single oral dose of 3 mg budesonide was given in the morning. In period 2, a 200-mg ketoconazole tablet was administered once daily in the morning on 4 consecutive days. On the fourth day, 3 mg budesonide was administered at the same time as the ketoconazole. In period 3, 200 mg ketoconazole was administered once daily in the evening on 4 consecutive days. On the fourth day, 3 mg budesonide was administered 12 hours before the ketoconazole. One-week washout periods separated the budesonide administrations. RESULTS: The mean area under the plasma drug concentration-time curve [AUC(0-24)] for budesonide was increased by 6.5 times when it was given simultaneously with ketoconazole. When the administrations of the two drugs were separated by 12 hours, the mean AUC(0-24) for budesonide was increased by only 3.8 times. CONCLUSION: This study shows that the capability of ketoconazole to inhibit the elimination of budesonide is significantly reduced (by 50%) by a 12-hour separation of the administration times.