Biotransformation in vitro of the 22R and 22S epimers of budesonide by human liver, bronchus, colonic mucosa and skin
Budesonide is a synthetic glucocorticosteroid used in the topical treatment of diseases such as rhinitis, asthma and psoriasis , which has also been introduced for the treatment of inflammatory bowel disease. This drug is characterized by a high local potency at the site of application with relatively low systemic activity after absorption. This high therapeutic ratio is probably explained by a combination of high affinity to the glucocorticoid receptor and rapid clearance from the systemic circulation, due to rapid biotransformation in the liver.
Budesonide contains an asymmetric 16α,17α-acetal group, resulting in an equal mixture of two epimers with 22R and 22S configuration. The 22R epimer has two to three times the anti-inflammatory potency of the 22S epimer. The oxidative metabolism of budesonide has been widely studied. The main metabolites formed from budesonide in human liver microsomes by isoenzymes of the cytochrome P450 3 A (CYP3A) subfamily have been identified as 6β-hydroxybudesonide and 16α-hydroxyprednisolone. The 6β-hydroxylation is a common metabolic pathway for glucocorticoids that proceeds equally with both epimers of budesonide; by contrast, the unusual ‘acetal splitting’ pathway is stereoselective for the 22R epimer. The anti-inflammatory potency of these two metabolites of budesonide is approximately two orders of magnitude lower than that of the parent drug. Although the oxidative metabolism constitutes the quantitatively more important elimination route of synthetic corticosteroids, the contribution of conjugation with sulphate may be also significant; hence, it has been shown that budesonide is metabolized by human liver sulphotransferase yet is not glucoronated.
The biotransformation of budesonide in the liver may differ from that observed in other organs. Thus, the lung catalyses the sulphation of budesonide but oxidative metabolism is apparently absent. Negligible biotransformation has been reported for budesonide in human skin. These findings indicate that the liver is the major organ of budesonide metabolism and explains the high local bioavailability of this steroid.
The aim of the present study was to assess the in vitro biotransformation of the two epimers of budesonide by measuring the decay of the concentration of unchanged steroid during incubation in 9000 g supernatant (S-9) fractions of human liver, bronchus, colonic mucosa and skin. These tissues were selected as relevant target organs because of the topical use of budesonide in the clinical practice. The S-9 fraction is suitable for this kind of study beacuse it contains both microsomal and soluble enzymes responsible for the biotransformation of glucocorticoids. In addition, we have measured the decay of the concentrations of unchanged steroid in primary cultures of human airway smooth muscle cells, in a transformed human airway epithelial cell line (BEAS-2B cells), and in human cultured hepatocytes.
Filed under: Metabolism