BIOTRANSFORMATION OF SEVOFLURANE BY RAT NEONATE LIVER SLICES

Sevoflurane [CF3-CH(OCH2F)-CF3] is biotransformed to inorganic fluorid e (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 wa s vaporized in sealed roller culture vials to produce a continuous sat urating dose (0.5 mM), After incubation, slices and incubation media w ere sonicated and centrifuged to remove debris. The supernatant fracti on was analyzed for F-, hexafluoroisopropanol, and hexafluoroisopropan ol-glucuronide conjugate. The metabolism of sevoflurane by liver slice s increased proportionately with time with a stoichiometric production (1:1) of hexafluoroisopropanol and F- in all age groups. Only glucuro nide conjugates of hexafluoroisopropanol were found. The rate of sevof lurane biotransformation measured as fluoride production was similar a mong slices prepared from all neonate age groups. Although no hexafluo roisopropanol-glucuronide was generated by slices from 4-, 6-, and and 8-day-old neonates, by day 21, 17% of the total hexafluoroisopropanal is glucuronidated. This contrasts with the lower levels of free hexaf luoroisopropanol 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.