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.
K
K
Morita
Y
Y
Sugiyama
M
M
Hanano
D000818:Animals; D001682:Biological Availability; D002855:Chromatography, Thin Layer; D004305:Dose-Response Relationship, Drug; D005268:Femoral Vein; D006923:Hymecromone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism*; D007275:Injections, Intravenous; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D011169:Portal Vein; D011485:Protein Binding; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors; D014468:Umbelliferones / Q000378:metabolism*
D014468:Umbelliferones; C019492:4-methylumbelliferyl sulfate; D006923:Hymecromone; C034888:4-methylumbelliferyl glucuronide