Cholic acid

Cholic acid is the predominant primary bile acid in man. In patients with inborn deficiency of 3β-Hydroxy-Δ⁵-C₂₇-steroid oxidoreductase and Δ⁴-3-Oxosteroid-5β-reductase, the biosynthesis of primary bile acids is reduced or absent. Both inborn diseases are extremely rare, with a prevalence in Europe of about 3 to 5 patients with 3β-Hydroxy-Δ⁵-C₂₇-steroid oxidoreductase deficiency per 10 million inhabitants, and an estimated ten-fold lower prevalence for Δ⁴-3-Oxosteroid-5β-reductase deficiency. In the absence of treatment, unphysiologic cholestatic and hepatotoxic bile acid metabolites are predominant in the liver, serum and urine. The rational basis for treatment consists of restoration of the bile aciddependent component of bile flow enabling restoration of biliary secretion and biliary elimination of toxic metabolites; inhibition of the production of the toxic bile acid metabolites by negative feedback on cholesterol 7α-hydroxylase, which is the rate-limiting enzyme in bile acid synthesis; and improvement of the patient’s nutritional status by correcting intestinal malabsorption of fats and fat-soluble vitamins.

Cholic acid, a primary bile acid, is partially absorbed in the ileum. The remaining part is transformed by reduction of the 7α-hydroxy group to deoxycholic acid (3α, 12α-dihydroxy) by intestinal bacteria. Deoxycholic acid is a secondary bile acid. More than 90% of the primary and secondary bile acids are reabsorbed in the ileum by a specific active transporter and are recycled to the liver by the portal vein; the remainder is excreted in the faeces. A small fraction of bile acids is excreted in urine.

No pharmacokinetic study data for cholic acid are available.

The available non-clinical data in the literature reveal no special hazard for humans based on studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction. The studies have however not been conducted to the same level of detail as for a pharmaceutical agent, as cholic acid is a physiological substance in animals and humans.

The intravenous LD₅₀ of cholic acid in mice is 350 mg/kg body weight. Parenteral administration may cause haemolysis and cardiac arrest. Administered orally, bile acids and salts generally have only a minor toxic potential. The oral LD₅₀ in mice is 1520 mg/kg. In repeated-dose studies, frequently reported effects of cholic acid have included decreased body weight, diarrhoea and liver damage with elevated transaminases. Increased liver weight and gallstones have been reported in repeated dose studies in which cholic acid was co-administered with cholesterol.

Cholic acid showed non-significant mutagenic activity in a battery of genotoxicity tests performed in vitro. Animal studies showed that cholic acid did not induce any teratogenic effect or foetal toxicity.