Effect of bile drainage and rifampicin, a pregnane X receptor agonist, on clinical and biochemical recovery of patients with obstructive cholestasis

The antibiotic rifampicin is identified as an activator of the nuclear receptor
pregnane X receptor (PXR). In vitro and in vivo studies have shown that
rifampicin, by being a PXR-ligand, has several possible pharmacological targets
for the treatment of cholestasis and thereby improves liver cell secretion and
cholestasis-induced pruritus. In a pilot study eight patients with progressive
hepatocellular secretory failure (serum bilirubin >255µmol/L) were successfully
treated with rifampicin, resulting in amelioration of bilirubin levels, and
pruritus also improved rapidly (article under submission). Rifampicin is
effective in cholestasis associated pruritus. It is shown that short-term
treatment with PXR agonists such as rifampicin is highly effective and safe.
Rifampicin for short duration, not longer than two weeks, is associated with a
low risk of hepatotoxicity, Rifampicin-induced hepatitis is only seen after 2-3
months of treatment.
Various cholestatic disorders are associated with pruritus. Recent results of
our group suggest that lysophosphatidic acid (LPA) and autotaxin (ATX) play a
critical role in cholestatic pruritus. However, the source of increased serum
ATX levels remains to be elucidated. Certain substances in bile may induce gene
expression of autotaxin. It is our aim to reveal the nature of these substances.
Without adequate therapy chronic cholestatic diseases can progress through
stages of inflammation and fibrosis to cirrhosis. The function of bile salts
during cholestasis is ambiguous: they act as pro-inflammatory agents on the one
hand and as signaling ligands via membrane bound and nuclear receptors on the
other hand. It is not known how hepatocytes and cholangiocytes gain resistance
against these noxious compounds in bile. Our group hypothesized an import role
for HCO3- secretion in the biliary tract as a defense mechanism against noxious
compounds in bile.

To study the effect of alleviation of obstructive cholestasis by biliary
drainage with or without rifampicin on serum bilirubin levels, quality of life,
itch intensity, and serum and/or biliary bile salt, ATX, LPA, FGF-19 and
biliary HCO3- levels in patients routinely undergoing biliary drainage via the
percutaneous or endoscopic route. Itch intensity will be quantified before and
during drainage with visual analogue scales (VAS).

Interventional study with invasive measurements

Rifampicin 150 mg twice a day for seven days and blood samples (3x 15 ml)

Patients who are admitted for PTC or ERC regularly stay for at least 24 hours
and are seen again in the outpatient clinic one week later. Blood sampling will
be performed at the day of PTC/ERCP, after 24 hours and after one and four
weeks. Six bile samples will be collected from the biliary drain in the first
24 hours and one sample a week later. The risks of the study are related to the
blood sampling; hematoma and phlebitis and side-effects of the use of
Rifampicin as described in the *Farmacotherapeutisch Kompas*: nausea, vomiting,
epigatrsic pain, elevated liver enzymes, jaundice, itch, headache and
dizziness. Rifampicin for short duration is associated with a low risk of
hepatotoxicity, rifampicin-induced hepatitis is only seen after 2-3 months of
treatment.