Effects of budesonide and prednisolone on hepatic kinetics for urea synthesis.
OBJECTIVE
Glucocorticoids upregulate hepatic urea synthesis and cause protein breakdown to prevail over synthesis, releasing amino acids into the blood stream and increasing the substrate supply for hepatic urea synthesis. Budesonide is a new generation glucocorticoid that may be used for treatment of inflammatory diseases, e.g. Crohn's disease and autoimmune hepatitis. Due to its extensive first-pass metabolism in the liver, it has a potential adverse effect profile superior to that of prednisolone. Little attention has been directed towards differences in nitrogen catabolic properties between budesonide and prednisolone.


METHODS
Eight normal male subjects (age 20-44 years; BMI 21.6-28.2 kg/m2) were randomly studied 3 times: 1) At baseline, 2) after 6 days of prednisolone (50 mg/day), and 3) after 6 days of budesonide (9 mg/ day). We measured urea nitrogen synthesis rates (UNSR) and blood alpha-amino-nitrogen (N) levels before, during, and after a 3-h constant infusion of alanine (2 mmol/(kg BW x h)). UNSR was estimated hourly as urinary excretion corrected for gut hydrolysis and accumulation in body water. The slope of the linear relationship between UNSR and amino-N concentration represents the hepatic kinetics of conversion of amino- to urea-N, and is denoted the functional hepatic nitrogen clearance (FHNC).


RESULTS
Prenisolone, but not budesonide, administration increased basal blood and amino nitrogen concentrations (3.5 +/- 0.1 mmol/l (control) vs 3.8 +/- 0.1 mmol/l (prednisolone) (p<0.05) and 3.6 +/- 0.1 mmol/l (budesonide) (NS). Basal UNSR values were significantly increased following prednisolone (23.3 +/- 6.5 (control) vs 51.2 +/- 6.3 (prednisolone) (p<0.05)), while budesonide had no effect on basal UNSR (33.7 +/- 4.2 (budesonide) (NS)). Prednisolone administration increased FHNC (from 24.6 +/- 4.7 l/h (control) to 47.3 +/- 5.9 l/h (prednisolone) (p<0.05). Budesonide administration did not significantly increase FHNC (33.7 +/- 4.2 l/h (budesonide), (vs control; p=0.12, vs prednisolone: p<0.05)).


CONCLUSIONS
Prednisolone administration led to increased levels of amino acids in blood and loss of N as urea, the latter in part due to a specific hepatic mechanism as shown by the increased FHNC. Budesonide led to unaltered levels of amino acids in blood, no changes in loss of N as urea, and unaltered hepatic kinetics for urea synthesis. Thus, oral budesonide administration had very limited effects on the hepatic contribution to nitrogen homeostasis and metabolism via urea synthesis, making treatment with budesonide superior to that of conventional glucocorticoids in this respect.
Wolthers
T
T
Department of Medicine V (Hepatology and Gastroenterology), Aarhus University Hospital, Kommunehospitalet, Denmark.
Hamberg
O
O
Grøfte
T
T
Vilstrup
H
H
D000328:Adult; D000588:Amines / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D019819:Budesonide / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005934:Glucagon / Q000097:blood; D005938:Glucocorticoids / Q000494:pharmacology; D019382:Human Growth Hormone / Q000097:blood; D006801:Humans; D007328:Insulin / Q000097:blood; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D011239:Prednisolone / Q000494:pharmacology*; D014508:Urea / Q000378:metabolism*
D000588:Amines; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D005938:Glucocorticoids; D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D019382:Human Growth Hormone; D019819:Budesonide; D007334:Insulin-Like Growth Factor I; D014508:Urea; D005934:Glucagon; D011239:Prednisolone