Biotransformation of sevoflurane by rat neonate liver slices

Sevoflurane [CF3-CH(OCH2F)-CF3] is biotransformed to inorganic fluoride (F-) and hexafluoroisopropanol, which forms a glucuronide conjugate. Although sevoflurane may be used in newborns without fully developed biotransformation activity, studies were performed using liver slices from rat neonates to determine sevoflurane disposition. Sevoflurane was vaporized in sealed roller culture vials to produce a continuous saturating dose (0.5 mM). After incubation, slices and incubation media were sonicated and centrifuged to remove debris. The supernatant fraction was analyzed for F-, hexafluoroisopropanol, and hexafluoroisopropanol-glucuronide conjugate. The metabolism of sevoflurane by liver slices increased proportionately with time with a stoichiometric production (1:1) of hexafluoroisopropanol and F- in all age groups. Only glucuronide conjugates of hexafluoroisopropanol were found. The rate of sevoflurane biotransformation measured as fluoride production was similar among slices prepared from all neonate age groups. Although no hexafluoroisopropanol-glucuronide was generated by slices from 4-, 6-, and 8-day-old neonates, by day 21, 17% of the total hexafluoroisopropanol is glucuronidated. This contrasts with the lower levels of free hexafluoroisopropanol typically seen in adults liver slices, wherein 51% of the hexafluoroisopropanol was glucuronidated. These studies indicate that sevoflurane is equally metabolized to hexafluoroisopropanol and F-, but a deficiency in glucuronosyltransferase occurs in neonates.