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4-Methylpyrazole (4-MP) is effectively removed by haemodialysis in the pig model
D Jacobsen1, J Ostensen, L Bredesen
1Department of Medicine, Ullevaal Hospital, University of Oslo, Norway.
Abstract:
The safety and pharmacokinetics of the alcohol dehydrogenase inhibitor 4-MP have recently been evaluated and its clinical use in ethylene glycol poisoning in France is promising. The dialysability of 4-MP is not known. This is important as hemodialysis is one of the cornerstones in the treatment of (late) ethylene glycol and methanol poisonings. We therefore studied the dialysability of 4-MP in the pig model. Anesthesized pigs (maintained on respirator) given 4-MP, 10 mg/kg, served as controls (n = 3) to the pigs (n = 3) given 15 mg/kg and hemodialyzed for 4 h. 4-MP plasma elimination curves for both groups were compared for 12 h and dialysance data calculated. 4-MP (MW 82) was removed by the same rate as urea (MW 60) by the 0.3 m2 dialysator, thus indicating no significant protein binding of 4-MP. The mean dialysance of 4-MP (and urea) in the three pigs were 61 (63), 51 (53) and 56 (48) ml/min, at a blood flow of 75 ml/min. The amount of 4-MP removed by hemodialysis in 4 h was 57-76 mg compared to a urinary excretion of 1-3 mg over 12 h. We conclude that the dialysability of 4-MP is significant and this must be taken into account when these two treatment procedures are combined.
Insights
The alcohol dehydrogenase inhibitor 4-MP is effectively removed by hemodialysis, similar to urea. This significant dialysability of 4-MP must be considered when combining treatments for poisoning.
Area of Science:
- Toxicology
- Pharmacokinetics
- Nephrology
Background:
- The alcohol dehydrogenase inhibitor 4-MP shows promise for treating ethylene glycol poisoning.
- Hemodialysis is crucial for managing severe ethylene glycol and methanol poisonings.
- The dialysability of 4-MP, essential for combined treatment protocols, was previously unknown.
Purpose of the Study:
- To investigate the dialysability of 4-MP in a relevant animal model.
- To compare the removal rate of 4-MP with urea during hemodialysis.
- To inform clinical practice regarding the combined use of 4-MP and hemodialysis.
Main Methods:
- Anesthetized pigs were administered 4-MP (10 mg/kg control, 15 mg/kg hemodialysis group).
- Hemodialysis was performed for 4 hours using a 0.3 m2 dialysator.
- Plasma elimination curves were analyzed over 12 hours, and dialysance was calculated.
Main Results:
- 4-MP (MW 82) demonstrated significant dialysability, comparable to urea (MW 60), indicating minimal protein binding.
- Mean 4-MP dialysance ranged from 51-61 ml/min at a blood flow of 75 ml/min.
- Hemodialysis removed 57-76 mg of 4-MP in 4 hours, significantly exceeding urinary excretion (1-3 mg over 12 hours).
Conclusions:
- 4-MP exhibits significant dialysability, comparable to urea.
- Hemodialysis is an effective method for removing 4-MP during treatment.
- The dialysability of 4-MP is a critical factor to consider when patients receive both 4-MP and hemodialysis concurrently.