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Anesthesiology:
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Sevoflurane, Fluoride Ion, and Renal Toxicity

Tinker, John H. MD; Baker, Max T. PhD

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To the Editor:--In a recent editorial regarding a study by Kharasch et al., [1] Brown [2] claims that sevoflurane is "biotransformed in a quantitative fashion similar to enflurane." How "similar" are they? In patients with renal impairment, sevoflurane administration resulted in average serum fluoride concentrations 85% greater than those given enflurane. [3] It has been reported that 8.1% of adult patients given sevoflurane had a serum fluoride concentration greater than 50 micro Meter. [4] What is the corresponding percentage for enflurane? Brown's contention that sevoflurane is not biotransformed to a greater extent than enflurane simply is not tenable.
Also, nothing was mentioned in the editorial about the other products of the biotransformation by cytochrome P450 of sevoflurane in vivo, namely hexafluoroisopropanol (HFIP) and the single carbon product that eventually results from the broken-off fluoromethoxy group of sevoflurane. Sevoflurane is unique compared to enflurane, isoflurane, and desflurane in that it contains a monofluorinated methoxy group rather than a difluoromethoxy group. The former by necessity undergoes a different mechanism of biotransformation after initial P450 metabolic attack.
The frenetic push toward convincing us that all this fluoride (and stoichiometric amounts of HFIP plus single carbon fragments) is not clinically important, is an attempt to obfuscate the fact that sevoflurane is an old anesthetic that moves us back in the direction of the heavily biotransformed agents of the past. How long did it take to report methoxyflurane nephrotoxicity after its introduction to clinical practice in 1959? Seven years. How many millions of anesthetics had been given with it by then before that particular toxicity became apparent? How long did it take before (most of us) recognized the existence of halothane-related hepatotoxicity? Are these toxicities related to biotransformation? Of course. Can we remotely predict these toxicities? No. Our recent strategy has been to develop volatile agents that undergo the lowest possible biotransformation, a strategy that makes sense.
The notion that somehow serum fluoride is no longer important in nephrotoxicity, to which Brown [2] and Kharasch et al. [1] have attached so much importance, obscures a more basic and important fact about this drug, which soon may be given to millions of Americans. Sevoflurane is heavily biotransformed. The editorialist's aversion to "shibboleths and jigsaw puzzles" [1] notwithstanding, the "fluoride issue" is not resolved.
Kharasch et al. [1] point out that inorganic fluoride is a nephrotoxin and cite the example that deuteration of methoxyflurane, which decreases methoxyflurane P450-dependent metabolism and fluoride release, diminishes renal toxicity. Despite their own citation, these authors attempted to dissociate serum fluoride concentrations from renal toxicity, by concluding that "neither peak systemic fluoride concentrations nor duration of fluoride increase alone can be applied nonselectively to all anesthetics to explain or predict nephrotoxicity." They imply that there may be some other metabolite or unknown metabolic consequence of methoxyflurane biotransformation that causes renal toxicity. After many years of methoxyflurane study, none has been found. Further, they suggest, without proposing any mechanism, that the small amount of fluoride produced in the kidney is relevant to nephrotoxicity, whereas the large amount of serum fluoride that passes through the kidney for excretion is irrelevant.
We moved steadily, after the first fluorocarbon anesthetics were introduced, toward agents with less biotransformation, for sound toxicologic reasons. Sevoflurane, which was rejected by Baxter-Travenol and Anaquest (Ohmeda) for clinical development, is a step backward, despite the likelihood that it will have desirable clinical characteristics.
John H. Tinker, M.D., Professor and Head.
Max T. Baker, Ph.D., Associate Professor, Department of Anesthesia, University of Iowa, College of Medicine, 200 Hawkins Drive, Iowa City, Iowa 52242-1009.
(Accepted for publication April 29, 1995.)
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REFERENCES

1. Kharasch ED, Hankins DC, Thummel KE: Human kidney methoxyflurane and sevoflurane metabolism: Intrarenal fluoride production as a possible mechanism of methoxyflurane nephrotoxicity. ANESTHESIOLOGY 82:689-699, 1995.

2. Brown BR Jr: Shibboleths and jigsaw puzzles (editorial). ANESTHESIOLOGY 82:607-608, 1995.

3. Melotte A, Verhaegen M, Conzen P, Van Aken H, Peter K: Plasma inorganic fluoride levels after sevoflurane or enflurane anesthesia in patients with renal impairment (abstract). ANESTHESIOLOGY 81:A368, 1994.

4. Stickler T, Callan C, Sayre J, Blahunka K, Prokocimer P: Incidence of inorganic fluoride concentrations greater or equal to 50 micro mol/l in sevoflurane comparative clinical studies (abstract). ANESTHESIOLOGY 81:A1283, 1994.

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