Chenodeoxycholic acid Other names: Chenodiol

Exogenous chenodeoxycholic acid is used as replacement therapy to restore the feedback inhibition lost due to the deficiency/absence of endogenous chenodeoxycholic acid. In CTX, a defect in the CYP27A1 gene results in a deficient mitochondrial sterol 27-hydroxylase enzyme. This deficiency blocks the synthesis of primary bile acids via the classical (neutral pathway) and the alternative (acidic) pathway. However, cholic acid is still formed via an alternate microsomal pathway. The net result is a total bile acid pool that is severely deficient in chenodeoxycholic acid but relatively enriched with cholic acid.

In CTX, deficiency of chenodeoxycholic acid causes a lack of feedback of cholesterol 7 alpha hydroxylase (CYP7A1) and HMG CoA reductase, causing increased production of atypical bile acids, bile alcohols and cholestanol that lead to the pathological consequences of the condition. Exogenous replacement with Chenodeoxycholic acid inhibits CYP7A1 (via nuclear receptor, FXR) and HMG CoA reductase, thus restoring the feedback inhibition.

The primary pharmacodynamic effects of chenodeoxycholic acid are:

1. Reduced production of cholesterol: reduces serum cholestanol (action on HMG CoA reductase).
2. Reduced production of cholestanol: reduces serum cholestanol (action on HMG CoA reductase and CYP7A1).
3. Reduced production of atypical bile alcohols and bile acids: through restoration of feedback inhibition of primary bile acid synthesis (action on CYP7A1).

Data exists only in the adult population.

Chenodeoxycholic acid is an endogenous bile acid in humans, which is tightly regulated by its secretion into bile via exporter pumps and detoxification by sulfation. In addition to sulfation, bile acid can also be detoxified through glucronidation.

Chenodeoxycholic acid given orally is absorbed in the small intestine. Reabsorption is not complete. A small portion of chenodeoxycholic acid is excreted with faeces.

After reabsorption in the intestine, the bile acid is nearly completely conjugated to the amino acids glycine and taurine and then excreted again in the bile.

In the intestine Chenodeoxycholic acid and its glycine or taurine conjugate are decomposed by bacteria. Deconjugation results in the free bile acid, oxidation in the 7-keto-lithocholic acid and lithocholic acid (3α-hydroxycholanic acid) is formed by elimination of the 7-hydroxy group. Whereas 7-keto-lithocholic acid can be formed partially in the colon and also in the liver to chenodeoxycholic acid and ursodeoxycholic acid (3α-, 7β-di-hydroxycholanic acid), lithocholic acid is absorbed to a small extent only and is thus largely lost with faeces.

Biological half-life of chenodeoxycholic acid is about 4 days.

Reabsorption of chenodeoxycholic acid is variable (29-84%). After treatment with chenodeoxycholic acid, the endogenous synthesis of the primary bile acids, cholic acid and chenodeoxycholic acid, is inhibited.

No formal preclinical safety studies have been conducted however data in the literature reveal no special hazard for humans based on conventional studies of single dose toxicity, repeated dose toxicity, genotoxicity, and carcinogenic potential.

Rodent and primate toxicity species lack efficient-sulfating capacity for conjugation of lithocholic acid, and therefore have shown hepatotoxicity. In contrast, Lithocholic acid sulfate conjugation in humans prevents the overt hepatotoxicity, as seen in animal toxicity species after repeat dosing.

Reproduction toxicity

Developmental toxicity studies in rats, hamsters and primates showed an absence of teratogenic effects. In rhesus monkey and baboon studies it was demonstrated that chenodeoxycholic acid dose to pregnant animals (at 5-120 mg/kg/day for rhesus monkey; at 18-38 mg/kg/day for baboons) produced liver pathology in the developing foetus. Pathological effects on adrenals and kidneys were also seen in rhesus monkey foetuses. Maternal effects in the rhesus monkeys, but not baboons, included diarrhoea, emesis, weight loss and reduction in food consumption.