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-hydroxybudesonide. Although it is apparent that the cytochrome P450 (CYP) system is involved, the actua l subfamily has not been identified. In attempts to do this, budesonid e 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 testest erone 6 beta-hydroxylation (correlation 0.98 and 0.95), a marker for C YP3A. When budesonide (10 mu M) was incubated with human liver microso mes in the presence of compounds known to interact with different isof orms or subfamilies of CYP, ketoconazole was found to be the strongest inhibitor of budesonide metabolism (IC50: approximately 0.1 mu M) fol lowed by troleandomycin (IC50: approximately 1 mu M), erythromycin, an d 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 sp ecifically inhibit the metabolism of budesonide. In addition, formatio n of the budesonide metabolites (16 alpha-hydroxyprednisolone and 6 be ta-hydroxybudesonide) was inhibited by antibodies against the CYP3A su bfamily, but not by antibodies against the CYP1A subfamily or control immunoglobulin G. We conclude that the formation of 16 alpha-hydroxypr ednisolone and 6 beta-hydroxybudesonide from budesonide is catalyzed b y isoenzymes within the CYP3A subfamily.