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Synthetic and semisynthetic opioids are pivotal in pain management and tackling opioid addiction. Semisynthetic opioids, including morphinans (morphine derivatives), oxycodone, oxymorphone, hydrocodone, and hydromorphone, have improved pharmacokinetic profiles compared to morphine. Additionally, heroin and 6-MAM (6-Monoacetylmorphine) show better CNS penetration than morphine due to heightened lipid solubility. Hydromorphone, a potent opioid, undergoes hepatic metabolism to form the active...
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In Vitro Hepatotoxicity of Routinely Used Opioids and Sedative Drugs.

Katharina Haller1, Sandra Doß2, Martin Sauer2,3,4

  • 1Department of Anesthesiology and Intensive Care Medicine, Charité Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany.

Current Issues in Molecular Biology
|April 26, 2024
PubMed
Summary

This study assessed the liver toxicity of common intensive care sedatives and opioids using a hepatocyte cell line. While most drugs showed minimal impact, sufentanil, remifentanil, and s-ketamine exhibited moderate in vitro hepatotoxicity, warranting caution in vulnerable patients.

Keywords:
analgosedationdrug-induced liver injury (DILI)hepatotoxicityintensive careopioidssedatives

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Area of Science:

  • Hepatology
  • Pharmacology
  • Toxicology

Background:

  • Hepatotoxicity of sedatives and opioids is not well-characterized, posing risks to critically ill patients with impaired liver function.
  • High cumulative doses of analgosedatives are common in intensive care, exacerbating potential liver damage.
  • Existing liver conditions in patients can increase susceptibility to drug-induced liver injury.

Purpose of the Study:

  • To determine the in vitro hepatotoxicity of commonly used intensive care sedatives and opioids.
  • To evaluate the effects of midazolam, propofol, s-ketamine, thiopental, fentanyl, remifentanil, and sufentanil on hepatocyte function.
  • To assess the impact of these drugs at clinically relevant and higher concentrations on cell viability and liver markers.

Main Methods:

  • Utilized a HepG2/C3A hepatocyte cell line biosensor for toxicity assessment.
  • Incubated cells with drugs for 2x3 days in cell culture medium or human plasma at Cmax, C5×, and C10× concentrations.
  • Measured cell count, viability, lactate dehydrogenase (LDH), mitochondrial dehydrogenase activity, cytochrome P450 1A2 (CYP1A2), and albumin synthesis.

Main Results:

  • All tested sedatives and opioids reduced hepatocyte viability; sufentanil and remifentanil showed more pronounced effects.
  • Sufentanil and remifentanil decreased cell count and increased LDH levels; midazolam and s-ketamine reduced mitochondrial activity.
  • Sufentanil and remifentanil decreased albumin synthesis at higher concentrations, while remifentanil and s-ketamine reduced CYP1A2 activity.

Conclusions:

  • No tested sedative or opioid demonstrated pronounced hepatotoxicity in vitro.
  • Sufentanil, remifentanil, and s-ketamine exhibited moderate hepatotoxic effects, necessitating cautious use in patients with pre-existing liver conditions.
  • Further research with complex models and pharmacovigilance is recommended, acknowledging the limitations of the HepG2/C3A cell line's metabolic capacity.