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Morphine effects on gentamicin disposition and toxicity in mice
A Hurwitz1, M Garty, Z Ben-Zvi
1Department of Medicine, University of Kansas Medical Center, Kansas City 66103.
Abstract:
Morphine has been shown to reduce renal and hepatic clearance of several xenobiotics in rodents. After iv administration of gentamicin, 10 to 30 mg/kg, its plasma levels were elevated in mice given morphine, 20 mg/kg sc. Plasma clearance of gentamicin was nearly halved by morphine, due primarily to lowering of the elimination constant of gentamicin from 0.03 to 0.02 min-1 (p less than 0.01). Morphine also significantly reduced urine levels of gentamicin and urine volume. In mice given naloxone, 2 mg/kg sc, morphine did not significantly raise plasma levels of gentamicin nor reduce its elimination into urine. Mice were made tolerant by morphine administration for 9 days at ascending doses to 100 mg/kg twice daily. An acute challenge with morphine, 20 mg/kg, was less effective in raising plasma levels of gentamicin or lowering its urinary elimination in tolerant mice than after chronic saline treatment. Partial tolerance to acutely administered morphine and reversal of morphine effects by naloxone suggest opioid receptor-mediated reduction of glomerular filtration by morphine in mice. Despite marked elevation of plasma gentamicin levels in morphine-treated mice, narcotic administration did not significantly increase the acute toxicity of a single dose of gentamicin. LD50 of acutely administered iv gentamicin was 51.6 mg/kg after saline and 45.3 mg/kg after treatment with morphine, 20 mg/kg sc. However, this dose of morphine enhanced the lethality of intravenously infused gentamicin. Morphine administration significantly reduced the dose of infused gentamicin needed to achieve the critical lethal plasma level.
Insights
Morphine significantly reduces the body's ability to clear gentamicin, increasing its plasma levels. This effect, mediated by opioid receptors, enhances gentamicin's lethality, especially with continuous infusion.
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.