Douwe Dekker1,2, Mirrin J Dorresteijn1,3, Marieke E B Welzen4, Simone Timman1, Peter Pickkers3, David M Burger4, Paul Smits1,2, Frank A D T G Wagener1,5, Frans G M Russel1. 1. Department of Pharmacology and Toxicology, Radboud University Medical Center, Nijmegen, The Netherlands. 2. Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. 3. Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. 4. Department of Pharmacy, Radboud University Medical Center, Nijmegen, The Netherlands. 5. Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, Nijmegen, The Netherlands.
Abstract
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.
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.
Authors: Marianne K Kringen; Armin P Piehler; Runa M Grimholt; Mimi S Opdal; Kari Bente F Haug; Petter Urdal Journal: PLoS One Date: 2014-02-28 Impact factor: 3.240
Authors: Douwe Dekker; Mirrin J Dorresteijn; Marieke E B Welzen; Simone Timman; Peter Pickkers; David M Burger; Paul Smits; Frank A D T G Wagener; Frans G M Russel Journal: Br J Clin Pharmacol Date: 2017-12-15 Impact factor: 4.335