Drugs which are cleared predominantly by forming acyl-
glucuronides undergo a futile cycle in which plasma drug clearance is a function of the formation, hydrolysis and renal clearance of the
glucuronide conjugate. The effect of impaired renal function, induced by
uranyl nitrate administration, on each component of this process was studied in rabbits using
diphenylacetic acid.
Uranyl nitrate administration produced a decrease in
creatinine clearance of approximately 70% and
diphenylacetic acid plasma clearance of approximately 35%. In healthy rabbits the primary determinant of
diphenylacetic acid net clearance was the very large component of
glucuronide renal clearance (14.10 ml/min/kg) compared with
glucuronide formation (4.79 ml/min/kg) or
glucuronide hydrolysis (2.56 ml/min/kg).
Uranyl nitrate treatment reduced both
creatinine clearance and the
glucuronide renal clearance by approximately 70%. Renal dysfunction had little effect on the hydrolysis clearance of the
glucuronide, but reduced its formation clearance by 22.8%. The reduction in plasma clearance of
diphenylacetic acid was a function of both the decrease in glucuronidation (60% contribution) and the decrease in renal clearance of the
glucuronide (40% contribution). This study supports the futile cycle mechanism of reversible
glucuronide conjugation for acyl-
glucuronides in general, and provides a mechanism for the impairment of the plasma clearance in
renal failure of drugs forming acyl-
glucuronides.