rifampin and Cholelithiasis

Rifampicin (RIFA) and ursodeoxycholic acid (UDCA) were found to stimulate different but complementary hepatobiliary detoxification pathways in gallstone patients.. To study whether single drug effects are sustained or even enhanced by combination of both drugs and whether possible effects are mediated by circulating fibroblast growth factor 19 (FGF19), which has recently been identified as a master regulator of bile acid biosynthesis.. 20 patients scheduled for laparoscopic cholecystectomy were randomized to a combination of UDCA (1 g/day during 3 weeks before surgery) and RIFA (600 mg/day during 1 week before surgery), or no treatment. Routine biochemistry, lipids, bile acid synthesis (7α-hydroxy-4-cholesten-3-one, C-4) and FGF19 were measured in serum. Bile acids were analyzed in serum and bile. A wedge liver biopsy was taken for determination of expression of hepatobiliary ABC transporters on mRNA and protein levels and of enzymes and regulatory transcription factors involved in the metabolism of biliary compounds on mRNA levels.. Combination treatment with both RIFA and UDCA significantly stimulated bile acid and bilirubin detoxification (CYP3A4, p < 0.001), conjugation (UGT1A1, p < 0.001) and elimination (MRP2, p < 0.05), as well as bile acid synthesis (p < 0.05), as compared to untreated controls. Notably, serum FGF19 levels in RIFA- and UDCA-treated patients did not differ from controls.. Combined treatment with RIFA and UDCA preserves the previously observed beneficial effects of single treatment with RIFA, including stimulation of bile acid synthesis. Most notably, the latter effect in humans is not mediated by FGF19.

Topics: Adult; Aged; Bile; Bile Acids and Salts; Biological Transport; Biopsy; Cholagogues and Choleretics; Cholelithiasis; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enzyme Inhibitors; Female; Humans; Inactivation, Metabolic; Liver; Male; Middle Aged; Rifampin; Ursodeoxycholic Acid; Young Adult

Rifampicin (RIFA) and ursodeoxycholic acid (UDCA) improve symptoms and biochemical markers of liver injury in cholestatic liver diseases by largely unknown mechanisms. We aimed to study the molecular mechanisms of action of these drugs in humans.. Thirty otherwise healthy gallstone patients scheduled for cholestectomy were randomized to RIFA (600 mg/day for 1 week) or UDCA (1 g/day for 3 weeks) or no medication before surgery. Routine biochemistry, lipids, and surrogate markers for P450 activity (4beta-hydroxy cholesterol, 4beta-OH-C) and bile acid synthesis (7alpha-hydroxy-4-cholesten-3-one, C-4) were measured in serum. Bile acids were analyzed in serum, urine, and bile. A wedge liver biopsy specimen was taken to study expression of hepatobiliary ABC transporters as well as detoxification enzymes and regulatory transcription factors.. RIFA enhanced bile acid detoxification as well as bilirubin conjugation and excretion as reflected by enhanced expression of CYP3A4, UGT1A1, and MRP2. These molecular effects were paralleled by decreased bilirubin and deoxycholic acid concentrations in serum and decreased lithocholic and deoxycholic acid concentrations in bile. UDCA on the other hand stimulated the expression of BSEP, MDR3, and MRP4. UDCA became the predominant bile acid after UDCA treatment and lowered the biliary cholesterol saturation index.. RIFA enhances bile acid detoxification as well as bilirubin conjugation and export systems, whereas UDCA stimulates the expression of transporters for canalicular and basolateral bile acid export as well as the canalicular phospholipid flippase. These independent but complementary effects may justify a combination of both agents for the treatment of cholestatic liver diseases.

Topics: Biological Transport; Cholelithiasis; Cholestasis, Intrahepatic; Dose-Response Relationship, Drug; Drug Administration Schedule; Elective Surgical Procedures; Female; Follow-Up Studies; Humans; Inactivation, Metabolic; Liver Circulation; Male; Middle Aged; Preoperative Care; Reference Values; Rifampin; Risk Assessment; Severity of Illness Index; Treatment Outcome; Ursodeoxycholic Acid

Topics: Cholagogues and Choleretics; Cholelithiasis; Cholestasis, Intrahepatic; Enzyme Inhibitors; Humans; Liver Circulation; Rifampin; Ursodeoxycholic Acid

Urinary bile acids from 20 patients treated with chenodeoxycholate, 18 treated with ursodeoxycholate, 15 treated with rifampicin and 8 patients with advanced cirrhosis were analyzed by gas-liquid chromatography and gas-liquid chromatography-mass spectrometry. Occurrence rates and amounts of three so-called unusual trihydroxy bile acids, hyocholate, ursocholate and omega-muricholate, were increased in patients treated with chenodeoxycholate, ursodeoxycholate or rifampicin and decreased in cirrhotic patients as compared with those in untreated healthy adults. These data suggest that chenodeoxycholate and ursodeoxycholate are hydroxylated to produce unusual trihydroxy bile acids in bile acid-loaded humans and that this metabolism may be related to the induction of hepatic microsomal enzymes by rifampicin. In contrast, the hydroxylation of chenodeoxycholate and ursodeoxycholate may be impaired by severe hepatic damage. Because the urine is a secretory pathway for internal bile acids, the occurrence of unusual trihydroxy bile acids in the urine may be used as an indicator of hepatic ability to metabolize "hydrophobic" dihydroxy bile acids to their secretory forms.

Topics: Bile Acids and Salts; Chenodeoxycholic Acid; Cholelithiasis; Chromatography, Gas; Deoxycholic Acid; Gas Chromatography-Mass Spectrometry; Humans; Hydroxy Acids; Liver Cirrhosis; Rifampin; Ursodeoxycholic Acid

Topics: Acute Disease; Bladder Exstrophy; Burns; Carcinoid Tumor; Cholelithiasis; Coronary Angiography; Coronary Artery Bypass; Coronary Disease; Emergencies; Esophageal and Gastric Varices; General Surgery; Methods; Necrosis; Pancreatitis; Rifampin; Transportation of Patients; Tuberculosis, Lymph Node; Tuberculosis, Osteoarticular; Vascular Surgical Procedures; Wounds and Injuries

Determination of the minimum inhibitory concentrations of rifamide necessary to inhibit organisms isolated from the biliary tract showed that the organisms were almost invariably sensitive to concentrations which are readily attainable in the biliary tract. Three cases of severe acute inflammation of the biliary tract were treated and this led to rapid clinical improvement. In 61 patients undergoing biliary surgery a random group was given rifamide 150 mg twice daily, beginning 24 hours before operation and continuing for three days afterwards. In the untreated group eight patients had infected bile at operation and five subsequently developed a wound infection. In the rifamide group three had infected bile at operation and only one developed a wound infection. A similar number of postoperative chest infections occurred in each group of patients. There is some evidence of reduction in length of hospital stay in the treated patients.

Topics: Acute Disease; Aged; Bile; Cholangitis; Cholecystitis; Cholelithiasis; Female; Gallbladder; Humans; Length of Stay; Male; Microbial Sensitivity Tests; Postoperative Complications; Respiratory Tract Infections; Rifampin; Surgical Wound Infection

Topics: Bile; Bile Duct Neoplasms; Cholangitis; Cholelithiasis; Cholestasis; Colitis, Ulcerative; Humans; Rifampin