Novel kinetic insights into treatment of unconjugated hyperbilirubinemia: phototherapy and orlistat treatment in Gunn rats.
Treatment with phototherapy or with the lipase inhibitor orlistat decreases plasma unconjugated bilirubin (UCB) concentrations in hyperbilirubinemic Gunn rats. We investigated the mechanism(s) underlying the effects of orlistat, phototherapy, and combined treatment, using steady-state 3H-UCB kinetics. After three weeks of treatment with orlistat (200 mg/kg chow), phototherapy (19 microW/cm2/nm) or combined treatment, tracer 3H-UCB was administered IV to treated and untreated (control) Gunn rats. Plasma samples and feces were collected every 12h for 60h, and bile for 30 min at 60h. The following results were obtained: 1) each treatment decreased plasma bilirubin levels compared with controls: orlistat- 19%, phototherapy-32%, combined treatment-53%; 2) plasma bilirubin concentrations were strongly, negatively correlated with fractional bilirubin turnover; 3) orlistat treatment induced net transmucosal excretion of UCB into the intestinal lumen, whereas phototherapy increased biliary UCB excretion rate; 4) all treatments profoundly increased the enterohepatic circulation of UCB derivatives, indicating enhanced metabolism by intestinal bacteria. In conclusion, orlistat and phototherapy lower plasma bilirubin concentrations in Gunn rats by increasing (net) intestinal influx of UCB, either by transmucosal excretion (orlistat), or increased biliary secretion (phototherapy). The mechanism of phototherapy and orlistat treatment involves increasing the availability of UCB in the intestinal lumen for fecal excretion and for metabolism by intestinal bacteria.
Pediatric Gastroenterology, Center for Liver, Digestive and Metabolic Disorders, University Medical Center Groningen, The Netherlands.
Anja M
AM
Hafkamp
Rick
R
Havinga
J Donald
JD
Ostrow
Claudio
C
Tiribelli
Lorella
L
Pascolo
Maarten
M
Sinaasappel
Henkjan J
HJ
Verkade
D000818:Animals; D001646:Bile / Q000737:chemistry; D001663:Bilirubin / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003131:Combined Modality Therapy; D004435:Eating / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005243:Feces / Q000737:chemistry; D006932:Hyperbilirubinemia / Q000378:metabolism / Q000628:therapy*; D007783:Lactones / Q000494:pharmacology / Q000627:therapeutic use*; D008049:Lipase / Q000037:antagonists & inhibitors; D008297:Male; D000077403:Orlistat; D010789:Phototherapy; D051381:Rats; D011911:Rats, Gunn; D014316:Tritium / Q000378:metabolism
D004791:Enzyme Inhibitors; D007783:Lactones; D014316:Tritium; D000077403:Orlistat; D008049:Lipase; D001663:Bilirubin