Abstract | BACKGROUND:
Methoxyflurane nephrotoxicity results from its metabolism, which occurs by both dechlorination (to methoxydifluoroacetic acid [MDFA]) and O-demethylation (to fluoride and dichloroacetic acid [ DCAA]). Inorganic fluoride can be toxic, but it remains unknown why other anesthetics, commensurately increasing systemic fluoride concentrations, are not toxic. Fluoride is one of many methoxyflurane metabolites and may itself cause toxicity and/or reflect formation of other toxic metabolite(s). This investigation evaluated the disposition and renal effects of known methoxyflurane metabolites. METHODS: Rats were given by intraperitoneal injection the methoxyflurane metabolites MDFA, DCAA, or sodium fluoride (0.22, 0.45, 0.9, or 1.8 mmol/kg followed by 0.11, 0.22, 0.45, or 0.9 mmol/kg on the next 3 days) at doses relevant to metabolite exposure after methoxyflurane anesthesia, or DCAA and fluoride in combination. Renal histology and function (blood urea nitrogen, urine volume, urine osmolality) and metabolite excretion in urine were assessed. RESULTS:
Methoxyflurane metabolite excretion in urine after injection approximated that after methoxyflurane anesthesia, confirming the appropriateness of metabolite doses. Neither MDFA nor DCAA alone had any effects on renal function parameters or necrosis. Fluoride at low doses (0.22, then 0.11 mmol/kg) decreased osmolality, whereas higher doses (0.45, then 0.22 mmol/kg) also caused diuresis but not significant necrosis. Fluoride and DCAA together caused significantly greater tubular cell necrosis than fluoride alone. CONCLUSIONS:
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Authors | Evan D Kharasch, Jesara L Schroeder, H Denny Liggitt, Dustin Ensign, Dale Whittington |
Journal | Anesthesiology
(Anesthesiology)
Vol. 105
Issue 4
Pg. 737-45
(Oct 2006)
ISSN: 0003-3022 [Print] United States |
PMID | 17006073
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Chemical References |
- Anesthetics, Inhalation
- Methoxyflurane
- Sodium Fluoride
- Dichloroacetic Acid
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Topics |
- Anesthesiology
(trends)
- Anesthetics, Inhalation
(pharmacokinetics, toxicity)
- Animals
- Biotransformation
- Dichloroacetic Acid
(metabolism, toxicity)
- Dose-Response Relationship, Drug
- Down-Regulation
(drug effects)
- Kidney
(pathology)
- Kidney Diseases
(chemically induced, pathology)
- Male
- Methoxyflurane
(pharmacokinetics, toxicity)
- Rats
- Rats, Inbred F344
- Sodium Fluoride
(metabolism, toxicity)
- Up-Regulation
(drug effects)
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