The Conjugative Metabolism of 4-Methylumbelliferone and Deconjugation to the Parent Drug Examined by Isolated Perfused Liver and in Vitro Liver Homogenate of Rats

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We examined the disposition of 4-methylumbelliferone (4-MU) and its conjugative metabolites, glucuronide (4-MUG) and sulfate (4-MUS), using a single-pass rat liver perfusion system. When 4-MU was delivered, the steady-state hepatic extraction ratio for 4-MU was very high (approximately 1.0) and its conjugative metabolites, 4-MUG and 4-MUS, appeared to a large extent in the effluent perfusate, The biliary excretion rate of the 4-MUG conjugated from 4-MU was 44% of the infusion rate at the steady-state, whereas those of 4-MU and 4-MUS were less than 1% of the infusion rate. When 4-MUG was delivered, the steady-state hepatic extraction ratio for 4-MUG was very low (<0.05) and the removal rae of 4-MUG from the perfusate was almost identical to the excretion rate of 4-MUG into the bile, while 4-MU and 4-MUS were slightly excreted into the bile (1% of the total biliary excretion rate), suggesting that a little deconjugation of 4-MUG to 4-MU occurred in the liver. Similarly, 4-MU and 4-MUS were not detectable in the effluent perfusate. The apparent extraction ratio (E_<app>) for the intracellularly conjugated 4-MUG was approximately twenty times higher than that for the pre-conjugated 4-MUG. This discrepancy between the values of E_<app> for the intracellularly conjugated and pre-conjugated 4-MUG might be attributed mainly to the diffusional barrier for the metaboliet between the blood and hepatocytes, as suggested in the previous simulation (J. Pharmacokin. Biopharm., 15,399 (1987)). On the other hand, when 4-MUS was delivered, 4-MUG appeared in the effluent perfusate, The biliary excretion rate of 4-MUG was approximately two times higher than that of 4-MUS (30% of the total biliary excretion rate), whereas the biliary excretion rate of 4-MU was negligible, suggesting that the deconjugation of 4-MUS to 4-MU occurred to a large extent in the liver. We also confirmed that the deconjugation of 4-MUG and 4-MUS occurred in the liver, using rat liver homogenate and its 9000×g fraction (pH7.4). On the assumption that the deconjugation was an apparent first-order process, the intrinsic clearance for the sulfatase was approximately eight times higher than that for glucuronidase, being consistent with the results of a single-pass perfusion.
社団法人日本薬学会の論文
1989-02-25

The Conjugative Metabolism of 4-Methylumbelliferone and Deconjugation to the Parent Drug Examined by Isolated Perfused Liver and in Vitro Liver Homogenate of Rats

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