Drug monograph: urosodiol - actigall
UROSODIOL - Actigall
Bile acid that may be useful for tx of hepatobiliary disease in dogs/cats. May also be used for cholesterol containing
Contraindicated: rabbits and other hindgut fermenters. Caution: complications associated with gallstones (e.g., biliary
obstruction, biliary fistulas, cholecystitis, pancreatitis, cholangitis).
Adverse effects: appears to be well tolerated in dogs/cats.
A naturally occurring bile acid, ursodiol, also known as ursodeoxycholic acid has a molecular weight of 392.6.
- Unless otherwise specified by the manufacturer, ursodiol capsules should be stored at room
temperature (15-30° C) in tight containers.
After oral administration, ursodiol suppresses hepatic synthesis and secretion of cholesterol. Ursodiol also decreases
intestinal absorption of cholesterol. By reducing cholesterol saturation in the bile it is thought that ursodiol allows solubilization of
cholesterol-containing gallstones. Ursodiol also increases bile flow and in patients with chronic liver disease it apparently reduces the
hepatocyte toxic effects of bile salts by decreasing their detergent action, and may protect hepatic cells from toxic bile acids (e.g.,
lithocholate, deoxycholate and chenodeoxycholate).
In small animals, ursodiol may be useful as adjunctive therapy for the medical management of
cholesterol-containing gallstones and/or in patients with chronic liver disease, particularly where cholestasis (bile toxicity) plays an
Ursodiol's benefit in treating canine or feline hepatobiliary disease is unknown at writing (studies are ongoing), but it may be of helpin slowing the progression of inflammatory hepatic disorders, particularly autoimmune hepatitis and acute hepatotoxicity.
Ursodiol is well absorbed from the small intestine after oral administration. In humans, up to 90% of dose is
absorbed. After absorption, it enters the portal circulation. In the liver it is extracted and combined (conjugated) with either taurine or
glycine and secreted into the bile. Only very small quantities enter the systemic circulation and very little is detected in the urine.
After each entero-hepatic cycle, some quantities of conjugated and free drug undergoes bacterial degradation and eventually most of
the drug is eliminated in the feces after being oxidized or reduced to less soluble compounds. Ursodiol detected in the systemic
circulation is highly bound to plasma proteins.
Contraindications/Precautions/Reproductive Safety -
Ursodiol is contraindicated in rabbits and other hindgut fermenters as it is
converted into lithocholic acid (toxic). Patients sensitive to other bile acid products may also be sensitive to ursodiol. The benefits of
using ursodiol should be weighed against its risks in patients with complications associated with gallstones (e.g., biliary obstruction,
biliary fistulas, cholecystitis, pancreatitis, cholangitis). While ursodiol may be useful in treating patients with chronic liver disease.
some patients may experience further impairment of bile acid metabolism.
Ursodiol's safety during pregnancy has not been unequivocally established, but studies in rats at doses up to 100 times those giventherapeutically in humans demonstrated no adversity to fetuses. It is unknown whether the drug enters breast milk, but no problemshave thus far been reported and it would unlikely be of concern (due to the very low systemic levels of the drug present).
Adverse Effects/Warnings -
While ursodiol use in animals has been limited, it appears to be well tolerated in dogs and cats.
Although hepatotoxicity has not been associated with ursodiol therapy, some human patients have an inability to sulfate lithocholic
acid (a naturally occurring bile acid and also a metabolite of ursodiol). Lithocholic acid is a known hepatotoxin; veterinary
significance is unclear. Diarrhea and other GI effects have rarely been noted in humans taking ursodiol. Ursodiol will not dissolve
calcified, radiopaque stones or radiolucent bile pigment stones.
Overdosage/Acute Toxicity -
Overdosage of ursodiol would most likely cause diarrhea. Treatment, if required, could include
supportive therapy; oral administration of an aluminum-containing antacid (e.g., aluminum hydroxide suspension); gastric emptying
(if large overdose) with concurrent administration of activated charcoal or cholestyramine suspension.
Drug Interactions -
Aluminum-containing antacids or cholestyramine-resin may bind to ursodiol, thereby reducing its efficacy.
For adjunctive treatment of chronic hepatitis:
a) 5 - 15 mg/kg PO divided ql2h, with immunosuppressive therapy. (Note: Use of this drug at this dose is preliminary, but promising)(Johnson and Sherding 1994)
b) 10 - 15 mg/kg PO once daily (Leveille-Webster and Center 1995); (Twedt 1999)
c) For use in chronic active hepatitis, fibrosis and cirrhosis. May use as primary or adjunctive therapy. Dose: 11 - 15.4 mg/kg POeither once daily or divided twice daily (Tams 2000)
For adjunctive treatment of chronic hepatitis:
a) 10 - 15 mg/kg PO once daily (Leveille-Webster and Center 1995); (Trepanier 1999)
b) For use in chronic active hepatitis, fibrosis and cirrhosis. May use as primary or adjunctive therapy. Dose: I I - 15.4 mg/kg POeither once daily or divided twice daily. Cats usually get 1/6th of a capsule mixed with a small amount of food. Cats may eat theirfood if drug sprinkled on top. (Tams 2000)
- 1) Efficacy (ultrasonography for gallstones; improved liver function tests for chronic hepatic disease); 2)
Monitoring of SGPT/SGOT (AST/ALT) on a routine basis (in humans these tests are recommended to be performed at the initiation
Of therapy and at I and 3 months after starting therapy; then every 6 months).
- Because ursodiol dissolves more rapidly in the presence of bile or pancreatic juice, it should be given with food.
Dosage Forms/Preparations/FDA Approval Status/Withholding Times -
Ursodiol Capsules 300 mg; Actigall (Ciba)(Rx)
Science, Art and Drug Discovery, A Personal Perspective Simon F. Campbell, PhD FRS Formerly Senior Vice President, WW Discovery, Pfizer Central Research The pharmaceutical industry is under intense pressure to increase productivity, and drug discovery is undergoing a paradigm shift whereby the explosion in genome sciences and new technologies is being harnessed to produce innovative th
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