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The metabolism of budesonide, (22RS)-16 alpha, 17 alpha-butylidenedioxy-11 beta,21-dihydroxypregna-1,4-diene- 3,20-dione, was studied in the 9000g supernatant fraction of livers from rat, mouse, and man. The two budesonide C-22 epimers produced different metabolites. This was explained by substrate-selective oxidation of the nonsymmetric 16 alpha, 17 alpha-acetal substituent. Epimer 22R gave 16 alpha-hydroxyprednisolone, while epimer 22S produced a metabolite tentatively identified as 23-hydroxybudesonide. Otherwise, budesonide followed the general metabolic pathways reported for synthetic glucocorticoids. Thus, oxidative metabolism predominated, 6 beta-hydroxybudesonide and delta 6-budesonide being identified in all investigated species. Reductive metabolism, giving 4,5 beta-dihydrobudesonide and 3,4,5 beta-tetrahydrobudesonide, was most pronounced in the rat. Rates and routes of budesonide metabolism were most similar in mouse and human livers. This implies that the mouse is a more relevant species than the rat in studies of the pharmacology and toxicology of budesonide.

Budesonide is a glucocorticoid of clinical interest for the topical treatment of skin and respiratory diseases. The in vitro liver biotransformation rate and in vivo systemic potency (thymus involution) of budesonide were studied in male and female rats. The biotransformation rate of [3H]-budesonide was about 4 times slower in the female than in the male rat liver 9000 g supernatant (t 1/2; 230 and 57 min, respectively). The systemic potency of budesonide after peroral or subcutaneous administration was higher (by factors of 6 and 2, respectively) in the female than in the male rat. These results suggest that the liver biotransformation rate of budesonide is of great importance in reducing its systemic action in the male rat.

Budesonide is a potent nonhalogenated glucocorticoid consisting of a 1/1 mixture of the two epimers 22R and 22S. The kinetics of these epimers were studied in six healthy male subjects after intravenous administration of 500 micrograms 3H-budesonide. Estimation of the epimer concentrations in plasma was made possible by development of an HPLC method for simultaneous separation and quantification. The plasma t 1/2, distribution volume (V beta), and plasma clearance for epimer 22R were (mean +/- SD) 2.66 +/- 0.57 hr, 425 +/- 100 l, and 117 +/- 40 l/hr. The corresponding values for epimer 22S were 2.71 +/- 0.69 hr, 245 +/- 38 l, and 67 +/- 19 l/hr. Differences in V beta and plasma clearance between the two were significant. The larger V beta noted for epimer 22R may be a result of higher tissue affinity. The high plasma clearance for both epimers should largely reflect their high rate of liver biotransformation.

The metabolic pathways of budesonide[(22RS)-16 alpha, 17 alpha-butylidenedioxy-11 beta, 21-dihydroxypregna-1,4-diene-3,20-dione] in human liver 9000g supernatant fraction were studied. A comparison was made between the in vitro metabolite pattern and the metabolite pattern in plasma obtained after iv administration of tritiated budesonide to man. No qualitative difference could be found, which indicates that the in vitro model is useful to predict results in vivo. The two major metabolites formed in vitro were identified by HPLC and mass spectrometry as 6 beta-hydroxybudesonide and 16 alpha-hydroxyprednisolone. Loss of the acetal group was not observed when desonide (11 beta,21-dihydroxy-16 alpha,17 alpha-isopropylidenedioxy-pregna-1,4-diene-3,20-dione) was incubated with human liver 9000g supernatant fraction. Neither could 16 alpha-hydroxyprednisolone be detected after incubation of the (22S)-epimer of budesonide with the same medium. The cleavage of the acetal moiety is therefore suggested to be the result of a substrate-selective metabolic pathway.

A moving belt interface was used to identify budesonide metabolites, obtained from rat and mouse liver incubations, by liquid chromatography/mass spectrometry (LC/MS). The metabolites were separated on a small-bore C18 column with an ethanol/water gradient as mobile phase at a flow rate of 0.2 ml min-1. A spray device was used for deposition of the aqueous solvent on to the belt. Chemical ionization mass spectra were obtained with methane as the reagent gas. Deuterium-labelled budesonide, which was used to facilitate metabolite identification by the isotope cluster technique, was found to be slightly separated from the unlabelled analogue on the LC column. Incubations were also performed under 18O2 to elucidate the mechanism of a new metabolic pathway (16 alpha, 17 alpha-acetal splitting) and to confirm the oxidative nature of reactions leading to hydroxylated metabolites. The moving belt LC/MS technique afforded higher sensitivity, and gave more abundant MH+ ions of the compounds studied, than previously found by direct probe mass spectrometry. Phthalate ester background, partly from the polymide belt, complicated the identification of minor metabolites.

Topical glucocorticoids usually have a high intrinsic glucocorticoid potency and may, after systemic uptake, induce side effects. The systemic inactivation of budesonide is rapid due to extensive liver biotransformation. The major metabolic pathway, 16 alpha, 17 alpha-acetal splitting, is unique for budesonide within this group of compounds. This biotransformation is catalyzed by microsomal monooxygenases and proceeds via hydroxylation and subsequent rearrangement to an intermediary ester. The ester is cleaved by hydrolysis to 16 alpha-hydroxyprednisolone and butyric acid. The hydrolysis product 16 alpha-hydroxyprednisolone has strongly reduced glucocorticoid activity.