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Parenteral bilirubin in healthy volunteers: a reintroduction in translational research
Author(s) -
Dekker Douwe,
Dorresteijn Mirrin J.,
Welzen Marieke E. B.,
Timman Simone,
Pickkers Peter,
Burger David M.,
Smits Paul,
Wagener Frank A. D. T. G.,
Russel Frans G. M.
Publication year - 2018
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.13458
Subject(s) - medicine , bilirubin , pharmacokinetics , adverse effect , asymptomatic , parenteral nutrition , bolus (digestion) , volume of distribution , perfusion , pharmacology , anesthesia , intensive care medicine
Aims Preclinical 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. Methods We 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). Results During 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. Conclusions Supported by previous reports, our data suggest that it is both feasible and safe to perform translational experiments with parenteral albumin bound bilirubin.