The influence of age on the distribution, metabolism and excretion of methoxyflurane in Fischer 344 rats: a possible relationship to nephrotoxicity.

Age as a factor in methoxyflurane nephrotoxicity was evaluated in Fischer 344 rats of various ages by determination of: 1) serum inorganic fluoride and methoxyflurane concentrations, and urinary inorganic fluoride excretion in methoxyflurane-exposed rats; 2) liver microsomal methoxyflurane defluorinase activity; and 3) distribution of injected sodium fluoride. Only rats in the youngest age group (6 weeks) did not develop nephrotoxicity after anesthesia. Older rats had a biphasic rather than a monophasic decay in serum methoxyflurane concentration and also had increased serum inorganic fluoride concentration and urinary inorganic fluoride excretion. Older rats also excreted a greater proportion of an injected dose of sodium fluoride compared to young rats. Microsomal methoxyflurane defluorinase specific activity was similar among rats of all ages. It is likely that increased availability of methoxyflurane due to its greater storage in fat led to more inorganic fluoride production in older compared to younger rats. Bone sequestration of inorganic fluoride in younger rats probably accounts for decreased serum inorganic fluoride levels in that group. Both factors cause significant differences in renal exposure to inorganic fluoride; thus the risk of nephrotoxicity is less in younger animals.