Deuterated methoxyflurane anesthesia and renal function in Fischer 344 rats

Area of Science:

• Toxicology
• Pharmacology
• Nephrology

Background:

• Methoxyflurane (MOF) is an anesthetic agent known to cause nephrotoxicity.
• Deuterated methoxyflurane (d4-MOF) was developed to potentially reduce toxicity.
• The role of metabolic activation in MOF-induced nephrotoxicity requires further elucidation.

Purpose of the Study:

• To compare the nephrotoxic potential of methoxyflurane (MOF) and deuterated methoxyflurane (d4-MOF).
• To investigate the effect of phenobarbital (PB) pretreatment on MOF and d4-MOF nephrotoxicity.
• To assess the relationship between inorganic fluoride (F-) production and renal impairment.

Main Methods:

• Six groups of Fischer 344 rats were used.
• Animals were exposed to air, MOF, or d4-MOF (0.5% v/v) for two hours.
• Some groups were pretreated with phenobarbital (PB).
• Serum and urinary inorganic fluoride (F-), serum urea nitrogen, and creatinine were measured.
• Urine volume and urinary F- excretion were quantified.

Main Results:

• Urinary F- excretion and urine volume were only slightly higher in MOF-exposed rats compared to d4-MOF exposed rats.
• Phenobarbital pretreatment significantly increased F- production and caused marked renal impairment in MOF-exposed rats.
• Phenobarbital pretreatment only slightly increased F- production and caused mild renal impairment in d4-MOF exposed rats.

Conclusions:

• A biologically significant difference in nephrotoxicity between MOF and d4-MOF was only evident in phenobarbital-pretreated animals.
• Phenobarbital pretreatment enhances MOF metabolism, leading to increased F- production and significant nephrotoxicity.
• Deuteration of methoxyflurane offers some protection against phenobarbital-induced nephrotoxicity.