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Updated: Apr 27, 2026

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
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Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities

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Pharmacokinetics and toxicity of repeated oral etoposide is altered by morphine coadministration in rats

Makoto Miyazaki1, Tomoko Kawase, Chisako Nishimura

  • 1Department of Pharmaceutics, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka, 569-1094, Japan, miyazaki@gly.oups.ac.jp.

European Journal of Drug Metabolism and Pharmacokinetics
|June 28, 2014
PubMed

Insights

Morphine (MOR) coadministration alters etoposide (ETP) absorption and toxicity in rats. MOR prolonged ETP-induced leukocyte reduction and decreased animal survival, indicating significant pharmacokinetic and toxicological interactions.

Area of Science:

  • Pharmacology
  • Toxicology
  • Drug Interactions

Background:

  • Etoposide (ETP) is a chemotherapy agent with variable oral absorption.
  • Morphine (MOR) is an opioid analgesic with potential to affect drug metabolism and transport.

Purpose of the Study:

  • To investigate the influence of repeated oral morphine (MOR) on the pharmacokinetics and toxicity of etoposide (ETP) in rats.
  • To elucidate the mechanisms underlying ETP-MOR interactions, potentially involving P-glycoprotein (P-gp).

Main Methods:

  • Rats received daily oral etoposide (ETP) with or without morphine (MOR) for a defined period.
  • Plasma ETP concentrations were measured to estimate pharmacokinetic parameters using Bayesian analysis and a 2-compartment model.
  • Leukocyte counts and animal viability were monitored to assess toxicity.

Main Results:

  • Morphine (MOR) coadministration prolonged ETP-induced leukopenia and decreased animal viability.
  • Repeated ETP dosing with MOR resulted in higher trough ETP concentrations and prolonged exposure compared to ETP alone.
  • MOR altered ETP's intestinal absorption rate and bioavailability, suggesting involvement of P-glycoprotein (P-gp).

Conclusions:

  • Repeated oral coadministration of morphine (MOR) significantly alters the pharmacokinetics and enhances the toxicity of etoposide (ETP) in rats.
  • These interactions are likely mediated by changes in ETP's intestinal absorption, potentially via P-glycoprotein (P-gp) modulation.
  • Clinicians should consider potential drug interactions when co-prescribing MOR and ETP, especially with oral administration.

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