Methoxyflurane

Fischer 344 (principal model) and Buffalo (strain comparison)^[1]

0.5% for 180 min; 0.75% for 360 min

inhalation; 180 min; 360 min

Fischer 344 and Buffalo rats metabolized Methoxyflurane to a greater extent than the other three rat strains, with higher serum and urine inorganic fluoride activity.
Only Fischer 344 rats developed functional and pathological evidence of a renal lesion after Methoxyflurane.
Renal functional and morphological changes were proportional to Methoxyflurane dose; polyuria after Methoxyflurane anesthesia or direct inorganic fluoride injection was ADH-resistant.
At 24 hr after 0.5% Methoxyflurane for 180 min, proximal convoluted tubular cells showed swollen mitochondria and some indentation of the nucleus.
At 24 hr after 0.75% Methoxyflurane for 360 min, there was pronounced mitochondrial swelling, degeneration, and rupture.
Injection of inorganic fluoride (NaF) produced a much greater degree of renal insufficiency in Fischer 344 rats than in Buffalo rats, and sodium fluoride injection in Fischer 344 rats resulted in dose-related polyuric renal insufficiency and pathological abnormalities similar to those after Methoxyflurane anesthesia.
Enzyme induction increased defluorination and nephrotoxicity, whereas SKF 525A (Proadifen hydrochloride) (HY-B1311) resulted in decreased defluorination and an attenuated renal lesion.
Gentamicin (HY-A0276A) and Methoxyflurane adverse renal functional and pathological effects were additive in Fischer 344 rats.

Sprague-Dawley (male, initial body weight 40-50 g)^[3]

0.13% (sleeping time); 0.13% followed 96 h later by 0.5% (tolerance experiment)

inhalation; 7 h/day for 1, 2, 3, 4, 5, 10, and 15 consecutive days; inhalation; 7 h/day for 10 consecutive days; then inhalation for 5 h 96 h later

Sleeping time after Methoxyflurane 0.13% was 96 minutes on day 1, 68 minutes on day 2, 43 minutes on day 3, 43 minutes on day 4, 34 minutes on day 5, 22 minutes on day 10, and 21 minutes on day 15.
Sleeping time decreased 79% between the first and fifteenth day of Methoxyflurane exposure.
After prior exposure to 0.13% Methoxyflurane 7 h/day for 10 days, exposure to 0.5% Methoxyflurane for 5 h resulted in 43% mortality (n=21).