Pharmacokinetic study of 4-methylumbelliferone in rats: influence of dose on its first-pass hepatic elimination.

The dose-dependent first-pass hepatic metabolism and pharmacokinetics of 4-methylumbelliferone (4-MU) were studied at four dose levels (17.6 micrograms-5.29 mg) in rats. 4-MU was given intravenously and intraportally to determine the availability of 4-MU. The availability increased from 0.18 to 1.31 when the dose was increased from 17.6 micrograms to 5.29 mg/rat. The total body plasma clearance of 4-MU was accounted for mostly by the hepatic conjugative metabolism. The contribution of renal clearance to total plasma clearance was 11-35%, depending on the dose. The marked dose-dependency of availability may thus be explained by the saturable conjugative metabolism of 4-MU.