Inhibition of beta-glucuronidase by natural glucuronides of kampo medicines using glucuronide of SN-38 (7-ethyl-10-hydroxycamptothecin) as a substrate.
1. 7-Ethyl-10-[4-(piperidino)-1-piperidino] carbonyloxycamptothecin (CPT-11), a potent anticancer agent currently under development for clinical use, is metabolized in vivo to 7-ethyl-10-hydroxycamptothecin (SN-38), which is subsequently conjugated to 7-ethyl-10-hydroxycamptothecin glucuronide (SN-38-glucuronide). The SN-38-glucuronide was hydrolysed by beta-glucuronidase from E. coli to aglycones and glucuronic acid. 2. Four purified natural glucuronides including baicalin, wogonoside, luteolin-3'-glucuronide, and glycyrrhizin, inhibited beta-glucuronidase using SN-38-glucuronide as substrate. The inhibition potencies of these natural glucuronides toward beta-glucuronidase were similar to that of saccharic acid 1,4-lactone. 3. These results indicate that plant materials of Kampo (Japanese herbal) medicines containing these glucuronides could be used in vivo to decrease the enterohepatic circulation of SN-38 and possibly that of other drugs.
Narita
M
M
Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Nagai
E
E
Hagiwara
H
H
Aburada
M
M
Yokoi
T
T
Kamataki
T
T
D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000494:pharmacology; D005965:Glucuronates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D005966:Glucuronidase / Q000037:antagonists & inhibitors* / Q000502:physiology; D000077146:Irinotecan; D007700:Kinetics; D013379:Substrate Specificity; D013997:Time Factors
D000972:Antineoplastic Agents, Phytogenic; D004365:Drugs, Chinese Herbal; D005965:Glucuronates; D000077146:Irinotecan; D005966:Glucuronidase; D002166:Camptothecin