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Budesonide exhibits typical glucocorticoid effects in that subcutaneous administration to adrenalectomized rats induced glycogen deposition in the liver, increased urinary volume and only slightly affected sodium excretion.

Whole body autoradiography in mice has shown budesonide and its metabolites to have a similar distribution pattern to other glucocorticosteroids with a high distribution to endocrine organs.

Data from preclinical investigations show a rapid elimination of the drug in all investigated species (rat, mouse, rabbit and dog). This rapid systemic elimination is attributed to extensive liver metabolism, mainly via oxidative and reductive pathways. No or insignificant metabolism of budesonide was found in target organs such as lung and skin. This is as a result of low amounts of the enzyme system (cytochrome P450 3A) which is responsible for the metabolism of budesonide in these organs.

The pathogenesis of Inflammatory Bowel Disease in general, and of Crohn's Disease (CD) in particular is not known. However, inflammatory immune responses are probably prominent features. Glucocorticosteroid drugs have the potential to interact with many aspects of this response, as they have a wide range of inhibitory activities against multiple cell types and mediators. Of importance in CD is probably the blocking of inflammatory cell influx, the inhibition of inflammatory mediator release by blockage of the arachidonic acid pathway, and the blocking of cytokine-mediated immune events.

The intrinsic potency of budesonide, measured as the affinity to the glucocorticoid receptor, is about 15 times higher than that of prednisolone. Clinical pharmacology and clinical data strongly indicate that budesonide capsules, at least partly, act topically.

Glucocorticosteroids increase blood neutrophils and decrease blood basophils, eosinophils and lymphocytes within 4 to 6 hours after administration to healthy volunteers. These effects are due to a transient redistribution of cells, with the values returning to normal within 24 hours. Treatment with budesonide capsules in daily doses of 3 to 15 mg for 8 weeks, and 3 to 6 mg for up to 1 year, affect circulating cells and systemic inflammatory markers (C-reactive protein and orosomucoid) to a very small extent.

The site of uptake of controlled ileal release budesonide has been studied in healthy subjects and in patients with Crohn's disease using inert ¹¹¹in-labelled pellets as markers of intestinal transit. These studies indicate that budesonide is continuously released during passage through the small intestines and ascending colon. In one study in 8 healthy subjects, 68% and 69% of totally absorbed budesonide was absorbed in the ileum and ascending colon in a fasting and fed state, respectively. In another study in 6 healthy subjects, the absorption values immediately before and after breakfast were 58% and 52%, respectively. In a study in 6 patients with Crohn's disease, 42% of budesonide, following administration after breakfast, was absorbed in the ileum and ascending colon. The lower mean value in patients as compared to healthy subjects may be explained by two patients, where the residence time in the ileum and the ascending colon was extremely short (1.6 h) as compared to an average of 13.8 h and 17.3 h in the rest of the patients and healthy volunteers, respectively.

The volume of distribution of budesonide in healthy subjects (range 2.2 to 3.9 L/kg), and in patients with CD (range 1.6 to 3.2 L/kg), is large and the plasma protein binding (85-90%) is extensive compared with other synthetic glucocorticosteroids. The free volume of distribution (i.e., the ratio between volume of distribution and free plasma) is high for budesonide. This reflects a high tissue affinity of the compound.

The half-life of budesonide after intravenous administration is 1.9-3.6 h in adults and shorter, 1.5 h, in children. In patients with CD, the plasma half-life after intravenous dosing is 2.4 h (range 2.1 to 2.8 h). After oral dosing with budesonide capsules, the mean terminal half-life for budesonide ranges between 3.0 and 5.1 h, with no discernible difference between patients and healthy subjects. Elimination of budesonide given as budesonide capsules is rate limited by its absorption, and the terminal half-life averages 4 hours.

The systemic clearance of budesonide (0.9-1.4 L/min) is high compared with other glucocorticosteroids. After oral dosing of budesonide capsules, the systemic availability in healthy subjects is approximately 10%, which is similar to oral dosing of plain micronized budesonide (6-13%) indicating complete absorption. After a single dose of budesonide capsules in patients with active CD, the systemic availability is approximately 20%. After repeated dosing for 8 weeks, the systemic availability approaches that in healthy subjects.

In human volunteers who inhaled tritiated budesonide, 31.8 ± 7.5% of the discharged radioactivity was recovered in the urine (within 96 hours of administration) while during the same period, 15.1 ± 4.3% of the radioactivity could be recovered in the faeces. In those subjects who took the compound orally, 45.0 ± 5.0% was recovered in the urine, 29.6 ± 2.5% in the faeces. Virtually no unchanged budesonide is excreted in the urine.

In vitro studies with human liver have shown that budesonide is rapidly metabolized to more polar compounds than the parent drug. Two major metabolites have been isolated and identified as 6b-hydroxybudesonide and 16a-hydroxyprednisolone. The glucocorticoid activity of these two metabolites was at least 100-fold lower than the parent compound as shown in the rat ear edema test. No qualitative differences between the in vitro and in vivo metabolic patterns could be detected. Negligible biotransformation was observed in human lung and serum preparations.

A complete toxicological program (acute, chronic, reproduction, mutagenicity and carcinogenicity studies) has been performed with budesonide after various routes of administration, such as oral, subcutaneous, epicutaneous and inhalation. Most of the studies were performed in rats and dogs. The toxicity of budesonide capsules, with a focus on the gastrointestinal tract, has been studied in Cynomolgus monkeys after repeated oral administration.

The acute toxicity studies with budesonide after oral and subcutaneous administration are summarized in Table 1.

Table 1. Acute toxicity of budesonide in mice and rats.

Surviving animals exhibited a marked decrease in body weight gain.

Table 2 summarizes the toxicity information from studies in which rats, rabbits and dogs received repeated oral, inhalation and subcutaneous administration of plain budesonide, as well as the toxicity of budesonide capsules after once daily oral administration of doses up to 5000 µg/kg/day, for 4 to 26 weeks to monkeys.

Table 2. Toxicity after repeated administration of budesonide to rats, rabbits, dogs and monkeys.

Effects on Pregnancy

Daily doses of 20, 100, and 500 mg/kg body mass were administered subcutaneously to pregnant rats during days 6-15 of gestation. In the high dose group, all of the rats showed a deteriorated general condition including piloerection, drowsiness, decreased food consumption and decreased body mass gain. Fetal loss was increased and pup masses decreased in comparison to the control group. The frequency of fetal abnormalities was also increased. Doses in excess of 100 mg/kg must be considered teratogenic in the rat.

Daily doses of 0.01, 0.05 and 0.1 - 0.25 mg/kg were administered by inhalation to pregnant rats during days 6-15 of gestation. At the highest dose a slight significant reduction in fetal weight gain was observed, but there was no evidence of any effect on fetal development attributable to budesonide at any dose level.

Daily doses of 5, 25, and 125 mg/kg body mass were administered subcutaneously during days 6-18 of gestation. In the low and medium dose groups, food consumption and body mass gain were decreased during the fourth gestational week. Some does also showed signs of diarrhea and vaginal bleeding. In the high dose group, all does aborted at the end of the gestation period. In the medium dose group, a marked increase in the frequency of abnormalities, mainly skeletal defects, was observed. Most commonly, defects were skull and vertebral abnormalities.

Effects on Fertility and General Reproductive Performance

To evaluate the effect of budesonide on fertility and general reproductive performance, daily doses of 0.01, 0.05, 0.19 mmol/kg were given subcutaneously to males for 9 weeks prior to and throughout mating. Females received the same doses for two weeks before, throughout gestation and up to 21 days postpartum. The offspring of the high dose group showed a decrease of peri- and post-natal viability. Dams showed a decrease in body mass gain.

Budesonide showed no mutagenic activity in the Ames Salmonella/microsome plate test or in the mouse micronucleus test.

The carcinogenic potential of budesonide was evaluated in long term mouse and rat studies.

Budesonide was administered in the drinking water for 91 weeks to three groups of CD^® -1 mice at dose levels of 10, 50 and 200 mg/kg/day.

A statistically significant dose-related decrease in survival was noted for the males only. All other evaluation criteria were comparable in all groups. Upon microscopic examination, a variety of spontaneous lesions was observed which were not related to treatment. No carcinogenic effect was present.

Three rat carcinogenicity studies have been performed. In the first study, budesonide was administered for 104 weeks in doses of 10, 25 and 50 mg/kg/day.

A small but statistically significant increase in gliomas was noted in male animals from the high dose group. These results were considered equivocal since the S-D rat is very variable with regard to spontaneous glioma incidence.

To elucidate these results, two further 104 week carcinogenicity studies with budesonide 50 mg/kg/day were performed, one using male S-D rats, and one using male Fischer rats (which have a lower and less variable incidence of gliomas). Prednisolone and triamcinolone acetonide were used as reference glucocorticoids in both studies.

The results from these new carcinogenicity studies in male rats did not demonstrate an increased glioma incidence in budesonide treated animals, as compared to concurrent controls or reference glucocorticosteroid treated groups.

Compared with concurrent control male S-D rats there was also an increased incidence of liver tumours in the mid- and high-dose groups in the original study. This finding was confirmed in all three steroid groups (budesonide, prednisolone, triamcinolone acetonide) in the repeat study in male S-D rats thus indicating a class effect of glucocorticosteroids.

There are few apparent toxicological effects of low doses of budesonide noted on the gastrointestinal tract which, together with the liver, is a body organ system that will be exposed to high concentrations of budesonide after oral administration of the drug.

Oral administration of budesonide to rats for 1 month disclosed no adverse effects on the gastrointestinal tract at doses up to 500 mg/kg although at 500 mg/kg atrophy of spleen and adrenals were noted as well as fat deposition in the liver, effects typical of a glucocorticoid. At 5000 mg/kg, ulcerations and bleeding of the gastrointestinal tract were noted as well as pronounced systemic toxicity.

Administration of budesonide, in the drinking water, to rats for 3 months, revealed at necropsy, stomach changes including raised white areas or nodules, dark ulcer-like areas, dark or dark-red foci and dark depressed areas among the female treated rats (50-700 mg/kg) and in one high-dosed male out of ten (700 mg/kg). No changes were noted in the control animals (both sexes). Similar stomach changes were also found in a three-month drinking water study in mice. No changes were noted at 10 mg/kg but these stomach changes were observed at 50 mg/kg in both sexes. However, no stomach lesions were reported among the high dosed male mice (700 mg/kg). A few control animals were also affected.

In a 12-month inhalation study (mainly oral/gastrointestinal deposition and absorption) in rats, histological examination disclosed the absence of bile duct hyperplasia of the liver at 50 mg/kg (high dose). This is a glucocorticoid effect since bile duct hyperplasia is a normal finding in the senescent rat. There were no adverse effects on the gastrointestinal tract at 50 mg/kg.

Budesonide given orally to dogs for 1 month disclosed a slight liver enlargement with increased glycogen deposition at 100 mg/kg. No adverse effects were noted on the gastrointestinal tract. A 12-month oral inhalation study in dogs (doses between 20-200 mg/kg) disclosed increased liver weight and glycogen deposition at 200 mg/kg. There were no adverse effects on the gastrointestinal tract at any dose level.

Oral administration of 100-1000 mg/kg/day budesonide capsules to Cynomolgus monkeys for 4 weeks disclosed no treatment-related clinical signs. Budesonide capsules given orally to Cynomolgus monkeys for 26 weeks disclosed no effects on the gastrointestinal tract at doses up to 5000 mg/kg/day.

Brogden RN, McTavish D.
Budesonide: An updated review of its pharmacological properties and therapeutic efficacy in asthma and rhinitis.
Drugs 1992;44(3):375-407.

Greenberg GR, Feagan BG, Martin F, Sutherland LR, Thomson ABR, Williams CN, Nilsson L-G, Persson T and the Canadian Inflammatory Bowel Disease Study Group.
Oral budesonide for active Crohn's disease.
N Engl J Med 1994;331:836-841.

Johansson SÅ, Andersson KE, Brattsand R, Gruvstad E, Hedner P.
Topical and systemic glucocorticoid potencies of budesonide, beclomethasone dipropionate and prednisolone in man.
Eur J Resp Dis 1982;63(22):74-82.

Lofberg R, Danielsson Å, Salde L.
Oral budesonide in active Crohn's disease.
Aliment Pharmacol Ther 1993;7:611-616.

Rutgeerts P, Löfberg R, Malchow H, Lamers C, Olaison G, Jewell D, Danielsson Å, Goebell H, Thomsen O, Lorenz-Meyer H, Hodgson H, Persson T, Seidegård C.
A comparison of budesonide with prednisolone for active Crohn's disease.
N Engl J Med 1994;331:842-845.

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