Paper

Acceleration of the Gastrointestinal Transit by Polyethylene Glycol Effectively Treats Unconjugated Hyperbilirubinemia in Gunn Rats

Frans J C Cuperus, Arjan A Iemhoff, Mariette Y M van der Wulp, Rick Havinga, Henkjan J Verkade^*

¹ Pediatric Gastroenterology, Department of Pediatrics, Center for Liver, Digestive, and Metabolic Dis, Netherlands

Correspondence to: Henkjan J. Verkade, Pediatric Gastroenterology, Dept. Pediatrics, University Medical Center Groningen, Room Y4.107a; PO Box 3001, Groningen, 9700 RB, Netherlands; h.j.verkade{at}med.umcg.nl

Accepted 6 October 2009

Background and aims: Several conditions that delay the gastrointestinal transit are associated with unconjugated hyperbilirubinemia. We hypothesized that the gastrointestinal transit time is directly related to plasma unconjugated bilirubin (UCB) concentrations, and that this relationship can be used to develop a new therapeutic strategy for severe unconjugated hyperbilirubinemia in the Gunn rat model.

Methods: Gunn rats received, for various time periods, oral polyethylene glycol (PEG) with or without conventional phototherapy treatment to accelerate, or oral loperamide to delay the gastrointestinal transit. Gastrointestinal transit time and UCB concentrations in plasma, feces, intestinal content and bile were determined.

Results: Within 36 hours, PEG administration accelerated the gastrointestinal transit by 45% and simultaneously decreased plasma UCB concentrations by 23% (each p<0.001). The decrease in plasma UCB coincided with an increased small intestinal UCB content (+340%, p<0.05) and an increased fecal UCB excretion (+153%, p<0.05). After two weeks, PEG decreased plasma UCB by 41% as single treatment, and by 62% if combined with phototherapy (each p<0.001). Loperamide delayed gastrointestinal transit by 57% and increased plasma UCB by 30% (each p<0.001). Dose-response experiments showed a strong, linear relation between the gastrointestinal transit time and plasma UCB concentrations (r=0.87, p<0.001).

Conclusion: Gastrointestinal transit time and plasma UCB concentrations are linearly related in Gunn rats. This relationship can be exploited by pharmacologically accelerating the gastrointestinal transit, which increases transmucosal UCB diffusion and thereby effectively treats unconjugated hyperbilirubinemia. Present results support the feasibility of PEG treatment, either solitary or combined with phototherapy, in patients with severe unconjugated hyperbilirubinemia.

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