Identification and Clearance Involved in the Formation of Glucuronides of RT-3003,a New Peripheral Blood Flow Enhancer, and Its Metabolite in Rats

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Glucuronides of RT-3003 and its metabolite (9-OH-RT-3003), which was hydroxylated at the 9 position on the benzene ring, were separated by HPLC and identified by liquid chromatography (LC)/MS/MS and NMR. The conjugation sites of these glucuronides were determined by nuclear Overhauser effects (NOE) irradiation; RT-3003 was conjugated at an alcoholic hydroxyl group of the hydroxymethyl moiety, and 9-OH-RT-3003 at a phenolic hydroxyl group on a benzene ring and at an alcoholic hydroxyl group of a hydroxymethyl moiety. On a reversed-phase HPLC of 9-OH-RT-3003,alcoholic glucuronide was eluted later than phenolic glucuronide, indicating the high hydrophobicity of alcoholic glucuronide. Clearance for the glucuronidation (Cl_G) of RT-3003 was lower than the summation of Cl_G for two types of glucuronidation of 9-OH-RT-3003. Cl_G of 9-OH-RT-3003 was high in phenolic glucuronide. The activity of UDP-glucuronyltransferase (UDPGT) for RT-3003 was 9.63 times that for 9-OH-RT-3003,and the activity ratio of the two types of glucuronidation of 9-OH-RT-3003 was similar to the ratio of the corresponding Cl_G. The difference between Cl_G and UDPGT activity is discussed in association with clearance for the hydroxylation and interaction of substrates with UDPGT.
公益社団法人日本薬学会の論文
2000-01-01