Budesonide is metabolized by cytochrome P450 3A (CYP3A) enzymes in human liver

Budesonide is a synthetic glucocorticosteroid that is commonly used in topical treatment of asthma and rhinitis. The main metabolites formed from budesonide in human liver microsomes have been identified as 16 alpha-hydroxyprednisolone and 6 beta-hydroxy-budesonide. Although it is apparent that the Cytochrome P450 (CYP) system is involved, the actual subfamily has not been identified. In attempts to do this, budesonide was incubated with microsomes from ten different human liver samples where various CYP activities had been rank ordered. We found a strong correlation between formation of the two main metabolites and testosterone 6 beta-hydroxylation (correlation 0.98 and 0.95), a marker for CYP3A. When budesonide (10 microM) was incubated with human liver microsomes in the presence of compounds known to interact with different isoforms or subfamilies of CYP, ketoconazole was found to be the strongest inhibitor of budesonide metabolism (IC50: approximately 0.1 microM) followed by troleandomycin (IC50: approximately 1 microM), erythromycin, and cyclosporin, all substances known to interact with CYP3A isoenzymes. Substances known to interact with CYP2C (sulfaphenazole, mephenytoin, and tolbutamide) and with CYP2D6 (bufuralol and quinidine) did not specifically inhibit the metabolism of budesonide. In addition, formation of the budesonide metabolites (16 alpha-hydroxyprednisolone and 6 beta-hydroxybudesonide) was inhibited by Antibodies against the CYP3A subfamily, but not by Antibodies against the CYP1A subfamily or control immunoglobulin G. We conclude that the formation of 16 alpha-hydroxyprednisolone and 6 beta-hydroxybudesonide from budesonide is catalyzed by isoenzymes within the CYP3A subfamily.