Parenteral bilirubin in healthy volunteers: a reintroduction in translational research

• DOI: 10.1111/bcp.13458
• Publication Date: 2017-10-25T11:46:39Z
• Authors: Douwe Dekker; Mirrin J. Dorrest...; Marieke E. B. Welzen; Simone Timman; Peter Pickkers; David M. Burger; Paul Smits; Frank A. D. T. G....; Frans G. M. Russel
• Keywords: Radboudumc 10: Reconstructive and regenerative medicine RIMLS: Radboud Institute for Molecular Life Sciences; Radboudumc 4: lnfectious Diseases and Global Health RIMLS: Radboud Institute for Molecular Life Sciences; Adult; Male; 0301 basic medicine; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Bilirubin; Radboudumc 11: Renal disorders RIMLS: Radboud Institute for Molecular Life Sciences; Healthy Volunteers; 3. Good health; Translational Research, Biomedical; 03 medical and health sciences; All institutes and research themes of the Radboud University Medical Center; Injections, Intra-Arterial; Injections, Intravenous; Humans; Radboudumc 0: Other Research RIHS: Radboud Institute for Health Sciences; Radboudumc 4: lnfectious Diseases and Global Health RIHS: Radboud Institute for Health Sciences; Hyperbilirubinemia

AimsPreclinical results suggest therapeutic potential of mild hyperbilirubinemia in T2DM and cardiovascular disease. Translational data are limited, because an appropriate bilirubin formulation for parenteral human use is lacking. Considering its use in both clinical practice and medical research in the past, we explored the feasibility to reintroduce parenteral bilirubin for translational experiments.MethodsWe developed a preparation method in accordance with good manufacturing practice and evaluated the parenteral applicability in healthy volunteers (n = 8). Explorative pharmacokinetic and safety data were compared to the results from a literature study on the former parenteral use of bilirubin. Bilirubin was administered intra‐arterially to raise the local plasma concentration in the forearm vascular bed (n = 4) and intravenously to raise the systemic plasma concentration (n = 4). Finally, pharmacokinetic characteristics were studied following a single bolus infusion (n = 3).ResultsDuring parenteral application, no side effects occurred. Adverse events mentioned during the two‐week observation period were in general mild and self‐limiting. Three more significant adverse events (appendicitis, asymptomatic cardiac arrhythmia and atopic eczema) were judged unrelated by independent physicians.A dose–concentration relationship appeared sufficiently predictable for both intra‐arterial and intravenous administration. In line with existing knowledge, bilirubin pharmacokinetics could be described best according to a two‐compartment model with a volume of distribution of 9.9 (±2.0) l and a total plasma clearance of 36 (±16) ml per minute.ConclusionsSupported by previous reports, our data suggest that it is both feasible and safe to perform translational experiments with parenteral albumin bound bilirubin.