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Pharmacological testing of therapeutics using normothermic machine perfusion: A pilot study of 2,4-dinitrophenol delivery to steatotic human livers

Lookup NU author(s): Dr Sam Tingle, Dr Emily ThompsonORCiD, Lucy BatesORCiD, Dr Ibrahim Ibrahim, Dr Olivier GovaereORCiD, Victoria Shuttleworth, Dr Lu Wang, Rodrigo Figueiredo, Dr Jeremy Palmer, Dr Yvonne BuryORCiD, Professor Quentin AnsteeORCiD, Colin Wilson

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Abstract

© 2022 International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.Introduction: Normothermic machine perfusion (NMP) provides a platform for drug-delivery. However, pharmacological considerations for therapeutics delivered during NMP are scarcely reported. We aimed to demonstrate the ability of NMP as a platform for pharmacological testing, using a drug which increases metabolism (2,4-dinitrophenol; DNP) as an example therapeutic. Methods: We performed 25 h of NMP on human livers which had been declined for transplant due to steatosis (n = 7). Three livers received a DNP bolus, three were controls, and one received a DNP infusion. Results: Toxicity studies revealed DNP delivery was safe, without hepatotoxic effects. The liver surface temperature was increased in the DNP group (p = 0.046), but no livers suffered hyperthermia—the mechanism of DNP toxicity in vivo. Pharmacokinetic studies revealed DNP elimination with first-order kinetics and 7.7 h half-life (95% CI = 5.1–15.9 hrs). The clearance of DNP in bile was negligible. As expected, DNP significantly increased oxygen consumption (p = 0.023); this increase was closely correlated with perfusate DNP concentration (r2 = 0.975; p = 0.002) and the effect was lost as DNP was eliminated by the liver. A DNP infusion rate, calculated using our pharmacokinetic data, successfully maintained perfusate DNP concentration. Discussion: Detailed pharmacological testing can be performed during NMP. Our therapeutic (DNP) is rapidly eliminated by the ex vivo liver, meaning the drug effect of increased metabolism is only transient. This demonstrates the importance of assessing pharmacokinetics when delivering therapeutics during NMP, especially for prolonged perfusion of organs with established roles in drug elimination. Rigorous pharmacological testing is needed to unlock the potential of NMP as a clinical drug-delivery platform.


Publication metadata

Author(s): Tingle SJ, Thompson ER, Bates L, Ibrahim IK, Govaere O, Shuttleworth V, Wang L, Figueiredo R, Palmer J, Bury Y, Anstee QM, Wilson C

Publication type: Article

Publication status: Published

Journal: Artificial Organs

Year: 2022

Pages: epub ahead of print

Online publication date: 12/05/2022

Acceptance date: 29/04/2022

ISSN (print): 0160-564X

ISSN (electronic): 1525-1594

Publisher: John Wiley and Sons Inc

URL: https://doi.org/10.1111/aor.14309

DOI: 10.1111/aor.14309

PubMed id: 35546070


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