Conjugative metabolism of 4-methylumbelliferone in the rat liver: Verification of the sequestration process in multiple indicator dilution experiments.

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Abstract
By means of the multiple indicator dilution (MID) method, the sequenstration process of 4-methylumbelliferone (4-MU), which is well known to be conjugated to glucuronide (4-MUG) and sulfate (4-MUS) in the rat liver, was found to be saturated as the dose was increased J. Pharmacokin. Biopharm., 15, 25 (1987). This observation might be attributed to the saturation of the conjugative metabolism. In the present study, using an in vivo tissue sampling single injection technique, we determined whether the sequestration process obtained by means of the MID method reflected the conjugative metabolism process. When the dose of 4-MU was increased from a low dose (110 .mu.g/rat) to a high dose (3200 .mu.g/rat). FDapp. 4-MUG and FDapp 4-MUS, which represent the fractions of the amounts of the formed 4-MUG and 4-MUS remaining in the liver, respectively, remarkably decreased. Since 4-MUG and 4-MUS formed from 4-MU have low diffusional clearances between the blood and hepatocytes, they are effectively trapped in the hepatocytes and therefore FDapp.4-MUG and FDapp.4-MUS represent the extents of the conjugative metabolism of 4-MU. Therefore, the dose-dependent change in the sequestration process was found to be attributable to the saturation of the conjugative metabolism. This observation confirms our previous hypothesis that the saturation of the sequestration process observed by using the MID method reflected that of the conjugative metabolism. Furthermore, according to the "sinusoidal" model, we simulated the time profiles of the amounts of drugs remaining in the liver, using parameters obtained form the MID data. The model, which has 20 sinusoidal compartments and can be regarded as identical to a "parallel tube" model, could reliably predict the time profiles of the amounts of drugs remaining in the liver.