Sulfation of Budesonide by Human Cytosolic Sulfotransferase, Dehydroepiandrosterone-Sulfotransferase (DHEA-ST)

Abstract

This article is available online at http://dmd.aspetjournals.org ABSTRACT:Budesonide, a synthetic glucocorticosteroid, is used in the treatment of asthma and allergic reactions, rhinitis, and inflammatory bowel disease. It is distributed as a mixture of two epimers, 22R and 22S, and has a high ratio of topical to systemic activity due to extensive first-pass metabolism to metabolites with minimal activity. Previous studies have shown that the epimers are metabolized by the cytochrome P450 monooxygenase system. Metabolism and inactivation of the epimers by the phase II enzymes has not been well characterized. This study describes the conjugation of budesonide by human cytosolic sulfotransferases (SULTs). Seven human SULTs were analyzed to determine which were capable of catalyzing the sulfation of the epimers of budesonide. Only dehydroepiandrosterone-sulfotransferase (DHEA-ST, SULT2A1) was capable of forming a sulfated budesonide product. The epimeric forms of budesonide display different kinetic activities with the 22R epimer having a 3.5-fold greater rate of sulfation activity than the 22S epimer. The structure of budesonide shows two hydroxyl sites that are potential sites for sulfate conjugation, but analysis by mass spectrometry indicates the formation of only a monosulfated budesonide product. A modeling approach was used to define the site of sulfation as that of the 21-hydroxyl group. Although sulfation of budesonide by DHEA-ST may not be an important factor in its use as an antiasthmatic, intestinal and hepatic sulfation will be important for its proposed systemic use as an anti-inflammatory agent.Budesonide (Fig. 1) is a synthetic glucocorticosteroid used in the treatment of asthma, rhinitis, and inflammatory bowel diseases. It has a high ratio of topical to systemic activity partly due to extensive first-pass metabolism in the liver to metabolites with minimal activity (Clissold and Heel, 1984). Budesonide is distributed as a mixture of two epimers, 22R and 22S. The epimeric mixture is a 1:1 ratio whereby the 22R epimer has been reported to have a potency that is 2-to 3-fold greater than the 22S epimer based on topical activity (Brattsand et al., 1982).Previous in vitro studies with human liver microsomes have demonstrated that the budesonide epimers are differentially metabolized by the cytochrome P450 monooxygenase system. Budesonide 22R is metabolized by CYP3A4 to two major metabolites, 16␣-hydroxyprednisolone and 6␤-hydroxybudesonide, whereas the 22S epimer is only metabolized to one major metabolite, 6␤-hydroxybudesonide (Jonsson et al., 1995). These metabolites are also present in high amounts in plasma and urine after administration of budesonide to humans (P. Anderson, AstraZeneca, unpublished results). In contrast to phase I metabolism, only limited information on the metabolism of budesonide by the phase II drug-metabolizing enzymes is available.

Interactions of the human cytosolic sulfotransferases and steroid sulfatase in the metabolism of tibolone and raloxifene

“…The plates were developed in methylene chloride:MeOH:ammonium hydroxide (85:15:5 by volume) and the radiolabeled sulfated products were localized by autoradiography. The sulfated products were scraped into scintillation fluid and radioactivity was determined by scintillation spectroscopy (16,21,30). Significant differences between reactions with and without STS was determined using the Students T-test.…”

“…Raloxifene is sulfated in vitro by at least seven expressed human SULT isoforms including SULTs 1E1 and 2A1 (12,17). SULT1E1 is responsible for the high affinity sulfation of estrogens (14,18,19) while SULT2A1 sulfates hydroxysteroids, bile acids and several therapeutic drugs (10,15,20,21). SULT1E1 and SULT2A1 are also of interest since SULT1E1 can form raloxifene disulfate and SULT2A1 can generate the 3-OH Tib disulfates (10,12).…”

In vitro drug–drug interactions of budesonide: inhibition and induction of transporters and cytochrome P450 enzymes

“…The activity of these metabolites is less than 1% of that of the parent compound, and they do not contribute further to the therapeutic effect of budesonide (Silverman & Otley, 2011). In vitro studies of the phase II metabolism of budesonide have demonstrated that it undergoes sulfation by cytosolic sulfotransferase enzyme 1A1 (Meloche et al, 2002); studies in lung tissue slices have also demonstrated the formation of fatty acid esters from budesonide (Nave et al, 2007). Budesonide is eliminated in the urine (60%) and faeces (40%) as metabolites (US Food and Drug Administration, 2009).…”

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“…Although it is rapidly and almost completely absorbed from the gastrointestinal tract, its bioavailability is low (about 10%) due to extensive first-pass metabolism in the liver. Furthermore, the metabolites produce less than 1% of the glucocorticoid activity when compared to the unchanged budesonide 1,2 . As with other glucocorticosteroids, long-term administration of systemic budesonide may cause many adverse effects such as hypothalamic-pituitary-adrenal suppression, growth retardation, and osteoporosis 3 .…”