Ursodeoxycholic acid (UDCA) is a white or almost white powder. It is practically insoluble in water, readily soluble in alcohol, sparingly soluble in acetone, in chloroform and in ether. It melts at 200 - 204°C. The IUPAC chemical name of UDCA is 3a, 7***946;-dihydroxy-5-cholan-24-oic acid. Its CAS number is 128-13-2. Ursofalk Capsule contains ursodeoxycholic acid 250mg, maize starch, colloidal silicon dioxide, magnesium stearate, gelatin and titanium dioxide.
PHARMACOLOGY
Pharmacodynamic properties
The mechanism of action of UDCA in liver and cholestatic disorders has not yet been explained totally. However, UDCA alters bile acid composition, resulting in increases in the concentration of UDCA and decreases in the concentrations of the more hydrophobic and potentially toxic bile acids, cholic and chenodeoxycholic acids. UDCA also has a choleretic effect, resulting in increased bile acid output and bile flow. There is some evidence for immunological effects, including a reduction of abnormal expression of HLA Class I antigens on hepatocytes and a suppression of immunoglobulin and cytokine production.
Pharmacokinetic Properties
UDCA occurs naturally in the body. After oral administration of a single 500 mg dose of UDCA to healthy volunteers, peak plasma concentrations were 7 to 16 µM. Tmax occurs at 60 minutes and a second peak plasma concentration occurs at 180 minutes. After oral administration of 250 mg, 500 mg, 1000 mg and 2000 mg single doses, respective absorption rates were 60.3%, 47.7%, 30.7% and 20.7% based on recovery from bile within 24 hours in patients with external biliary drainage.
In plasma, protein binding is 96 - 98%.
First pass extraction of UDCA from the portal vein by the liver ranges from 50 - 70%. UDCA is conjugated to glycine and taurine and then excreted into bile and passes to the small bowel. In the intestine, some conjugates are deconjugated and reabsorbed in the terminal ileum. Conjugates may also be dehydroxylated to lithocholic acid, part of which is absorbed, sulphated by the liver and excreted by the biliary tract. In healthy volunteers given UDCA 500 mg with 14C tracer, 30 - 44% of the dose was excreted in faeces in the first three days as UDCA (2 - 4%), lithocholic acid (37%) and 7-ketolithocholic acid (5%).
The biological half-life of orally administered UDCA is 3.5 - 5.8 days.
In patients with severe liver disease, renal excretion becomes a major route for elimination of bile acids.
Clinical Trials
Primary Biliary Cirrhosis
Five pivotal randomised, double-blind control studies examined the efficacy of ursodeoxycholic acid in the treatment of primary biliary cirrhosis. All 5 trials were of at least 2 years follow-up. Four of the five studies used a dosage in the range of 10 - 15 mg/kg/day; the fifth trial used a significantly lower dose of 7.7 ± 0.2 mg/kg/day. Significant improvement in some or all biochemical tests of liver function was shown in subjects given UDCA during the treatment period. Symptom improvement or improvement in histology were not consistently reported with UDCA but longer survival without liver transplantation was reported in two long term studies. One of the studies reported that the efficacy of UDCA in patients with primary biliary cirrhosis was greater in patients with less advanced disease (entry bilirubin < 2mg/dL; histological stage I or II) compared to patients with more advanced disease.
Primary Sclerosing Cholangitis
Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterised by inflammation, fibrosis, and destruction of the large intra- and extra-hepatic bile ducts. One pivotal randomised, double-blind placebo-controlled study examines the efficacy of UDCA in the treatment of PSC in 105 patients over 2 years. The dosage used was in the range of 13 - 15 mg/kg/day. Irrespective of initial histological stage, UDCA had no effect on time to treatment failure and survival, without liver transplantation. Serum bilirubin, ALP and AST improved, but UDCA was not associated with a significant improvement in symptoms or histological score. In three smaller randomised, double-blind, placebo-controlled studies, UDCA similarly showed significant improvement in liver biochemistry (in 2 of the studies) when compared to placebo, but did not significantly improve symptom scores. One study found significant improvement in some liver histological features in the patients treated with UDCA. These trials used UDCA doses ranging from 10 - 15 mg/kg/day.
Cystic fibrosis-related cholestasis
Cystic fibrosis (CF) is a hereditary disease with multiorgan involvement. Clinical liver disease is rare although many patients may have biochemical evidence of cirrhosis.
One double-blind, placebo-controlled, study randomised 55 patients with CF to UDCA 900 mg/day or placebo for one year. In addition, taurine supplements or placebo were randomly assigned. Efficacy was assessed by improvements in clinically relevant and nutritional parameters, and liver biochemistry. After one year, the UDCA group had significant improvement in GGT and 5'-nucleosidase but not AST or ALT. However, there was a deterioration of overall clinical condition, as measured by the Shwachman-Kulcycki score in those receiving placebo compared to the UDCA group.
In a dose comparison study, UDCA 20 mg/kg/day for 12 months resulted in a more pronounced improvement in GGT and ALT compared to UDCA 10 mg/kg/day. Improvements in AST and ALP were comparable. Although this study suggested a possible benefit with higher drug doses in resolving liver biochemistry, whether UDCA improves quality of life, histology, or survival is unknown.
INDICATIONS
URSOFALK is indicated in the treatment of chronic cholestatic liver diseases.
CONTRAINDICATIONS
URSOFALK must not be used in the presence of acute inflammation of the gall bladder and bile ducts; and obstruction of the biliary tract (common bile duct).
