Novel Kinetic Insights into Treatment of Unconjugated Hyperbilirubinemia: Phototherapy and Orlistat Treatment in Gunn Rats

Abstract

ABSTRACT: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 3 H-UCB kinetics. After three weeks of treatment with orlistat (200 mg/kg chow), phototherapy (19 W/cm 2 /nm) or combined treatment, tracer 3 H-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.

Orlistat Treatment of Unconjugated Hyperbilirubinemia in Crigler-Najjar Disease: A Randomized Controlled Trial

“…Previously, we showed a similar relationship between plasma UCB concentration and fecal fat excretion in Gunn rats (18). The hypobilirubinemic effect of orlistat in Gunn rats is partially due to increased metabolism of UCB to derivatives (17). Others have also shown the importance of the intestinal microflora for UCB metabolism (26).…”

Combined Treatment Strategies for Unconjugated Hyperbilirubinemia in Gunn Rats

“…Phototherapy, the routine treatment for neonatal jaundice, has been shown to exert its hypobilirubinemic effect by conversion of UCB into photoisomers (26). Experimental oral treatments, such as orlistat, UDCA, or CaP, are thought to bind UCB within the gut lumen, thereby preventing its reabsorption and interrupting its enterohepatic circulation (13,27,34). Interestingly, both phototherapy and oral treatments have also been suggested to accelerate the gastrointestinal transit.…”

“…Bilirubin, Ur, Creat, AST, and ALT were determined by routine spectrophotometry on a P800 unit of a modular analytics serum work area from Roche Diagnostics Ltd. (Basel, Switzerland). We previously found that the total bilirubin concentration in Gunn rat plasma, measured by spectrophotometry, equaled the total UCB concentration, measured by high-liquid performance chromatography after chloroform extraction (17,27).…”

“…The light intensity of phototherapy was measured by a Dale 40 phototherapy radiometer (Dale Technologies, Carson City, NV) at 20 cm distance from the light source and was set to 17 W/cm 2 /nm. Gunn rats, shaven on their backs and flanks every 7 d, received continuous phototherapy (27).…”

“…The efficacy of phototherapy ϩ PEG treatment, which resulted in a final 67% decrease in plasma bilirubin levels, might well result from the distinct mechanisms by which phototherapy and PEG decrease plasma bilirubin levels. Phototherapy predominantly decreases plasma bilirubin levels by enhancing its disposal via the bile (26), whereas oral treatments, including PEG, selectively enhance net bilirubin diffusion from the blood into the intestinal lumen (13,27). We and others have demonstrated in 3 H-labeled bilirubin studies that a maximal therapeutic effect often results from combining therapies that enhance distinct pathways for bilirubin disposal (13,26,27).…”