Morphine effects on gentamicin disposition and toxicity in mice

Area of Science:

• Pharmacology
• Toxicology
• Nephrology

Background:

• Morphine is known to affect the clearance of foreign substances (xenobiotics) in rodents.
• Opioid receptors play a role in regulating physiological processes, including drug metabolism and excretion.

Purpose of the Study:

• To investigate the impact of morphine on the pharmacokinetic profile and toxicity of gentamicin in mice.
• To explore the role of opioid receptors in morphine-induced alterations of gentamicin clearance.

Main Methods:

• Gentamicin was administered intravenously to mice, with some groups receiving concurrent subcutaneous morphine.
• Plasma and urine levels of gentamicin were measured over time.
• Drug elimination constants and urine volumes were calculated.
• Tolerance to morphine was induced, and its effects on gentamicin were re-evaluated.
• Naloxone was used to assess the involvement of opioid receptors.
• Acute toxicity (LD50) and lethality of infused gentamicin were determined in the presence and absence of morphine.

Main Results:

• Morphine (20 mg/kg) significantly elevated gentamicin plasma levels and reduced its plasma clearance by nearly half.
• Morphine decreased gentamicin elimination into urine and reduced urine volume.
• Naloxone reversed the effects of morphine on gentamicin levels and elimination.
• Tolerance to morphine reduced its impact on gentamicin pharmacokinetics.
• While acute toxicity of a single gentamicin dose was not significantly increased, morphine enhanced the lethality of continuously infused gentamicin.

Conclusions:

• Morphine reduces gentamicin renal clearance in mice, likely through an opioid receptor-mediated mechanism affecting glomerular filtration.
• This pharmacokinetic alteration by morphine increases the risk of gentamicin-induced toxicity, particularly with sustained exposure.
• The findings highlight potential drug-drug interactions between opioids and nephrotoxic antibiotics.