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The Effects of Fentanyl on Hepatic Mitochondrial Function

Djafarzadeh, Siamak PhD; Vuda, Madhusudanarao PhD; Jeger, Victor MD, PhD; Takala, Jukka MD, PhD; Jakob, Stephan M. MD, PhD

doi: 10.1213/ANE.0000000000001280
Anesthetic Pharmacology: Original Laboratory Research Report

BACKGROUND: Remifentanil interferes with hepatic mitochondrial function. The aim of the present study was to evaluate whether hepatic mitochondrial function is affected by fentanyl, a more widely used opioid than remifentanil.

METHODS: Human hepatoma HepG2 cells were exposed to fentanyl or pretreated with naloxone (an opioid receptor antagonist) or 5-hydroxydecanoate (5-HD, an inhibitor of mitochondrial adenosine triphosphate (ATP)-sensitive potassium [mitoKATP] channels), followed by incubation with fentanyl. Mitochondrial function and metabolism were then analyzed.

RESULTS: Fentanyl marginally reduced maximal mitochondrial complex–specific respiration rates using exogenous substrates (decrease in medians: 11%–18%; P = 0.003–0.001) but did not affect basal cellular respiration rates (P = 0.834). The effect on stimulated respiration was prevented by preincubation with naloxone or 5-HD. Fentanyl reduced cellular ATP content in a dose-dependent manner (P < 0.001), an effect that was not significantly prevented by 5-HD and not explained by increased total ATPase concentration. However, in vitro ATPase activity of recombinant human permeability glycoprotein (an ATP-dependent drug efflux transporter) was significantly stimulated by fentanyl (P = 0.004).

CONCLUSIONS: Our data suggest that fentanyl reduces stimulated mitochondrial respiration of cultured human hepatocytes by a mechanism that is blocked by a mitoKATP channel antagonist. Increased energy requirements for fentanyl efflux transport may offer an explanation for the substantial decrease in cellular ATP concentration.

Supplemental Digital Content is available in the text.Published ahead of print April 13, 2016

From the *Department of Intensive Care Medicine, Inselspital, Bern University Hospital, University of Bern, Switzerland; and Department of Clinical Research, Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.

Accepted for publication January 29, 2016.

Published ahead of print April 13, 2016

Funding: Support was provided by the Swiss National Science Foundation (SNSF) (grant no. 32003B_127619/1) and by an MD-PhD scholarship received by Dr. Jeger from the SNSF (grant no. 133901).

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

Reprints will not be available from the authors.

Address correspondence to Stephan M. Jakob, MD, PhD, Department of Intensive Care Medicine, Inselspital, Bern University Hospital, University of Bern, CH-3010 Bern, Switzerland. Address e-mail to

© 2016 International Anesthesia Research Society