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FUROSEMIDE GLUCURONIDATION IN INFANTS: IMPLICATIONS OF BETA-GLUCURONIDASE RESISTANT ISOMER FORMATION

Furosemide (F) glucuronidation has been inconclusively suggested to affect the age-related increase in F clearance in infants. A specific high pressure liquid chromatography (HPLC) method for direct determination of furosemide glucuronide (FG) was developed. This method revealed the presence of beta-glucuronidase resistant (BG-R) isomers of FG, a phenomenom previously described for ester glucuronides. At neutral to mild alkaline conditions (pH 6.8-8.6, 37°C, 3 hours) FG, purified from both human urine and incubation of F and uridine diphosphoglucuronic acid in rat liver microsomes, partially isomerized to BG-R forms. Sodium hydroxide (NaOH) hydrolysis recovered all the F from all FG forms. In 6 sick infants (EGA 28-35 wks; ages 7-80d) given 1 or 2 mg/kg F i.v., 12 hour urine collections for determination of total FG (NaOH sensitive), BG sensitive FG (bovine enzyme, pH 5.2, 37°C, 1 hr) and direct FG measurement (HPLC) showed: (1) FG accounted for 7-37% of urinary F excretion, (2) urine kept at pH ≤ 5 had no significant difference in FG content by any of the assays, and (3) urine stored frozen at pH 7.0 contained 0-69% of FG as BG-R isomers. We conclude: (1) BG resistant isomers of FG may form under physiological conditions, and (2) formation of these isomers can occur in vitro as a methodologic artifact. We speculate that the possible in vivo formation of BG resistant isomers of FG has implications for F enterohepatic cycling and disposition.