title: Interaction of Rhei Rhizoma extract with cytochrome P450 3A and efflux transporters in rats.
abstract: Traditional Chinese herbal medicines are frequently prescribed in pharmacotherapy in Japan. In the present study, we evaluated the possible interaction of several herbal extracts including Rhei Rhizoma extract with cytochrome P450 (CYP) 3A and efflux transporters such as P-glycoprotein and multidrug resistance-associated protein (MRP) 2. Rhei Rhizoma extract (100 microg/ml) significantly suppressed the CYP3A-mediated 6beta-hydroxylation of testosterone in hepatic microsomes, and increased the extent of bioavailability of midazolam, a typical CYP3A substrate, in rats. Also, Rhei Rhizoma extract (300 microg/ml) significantly suppressed P-glycoprotein-mediated efflux transport of rhodamine 123 (Rho123) in rat everted intestine. In an in-vivo study, Rhei Rhizoma extract added to intestinal perfusate at a concentration of 300 microg/ml significantly suppressed the intestinal exsorption of Rho123, though it exerted no effect on the biliary excretion of Rho123. Furthermore, the in-vitro and in-vivo MRP2-mediated intestinal efflux of 2,4-dinitrophenyl-S-glutathione was significantly suppressed by Rhei Rhizoma extract (1000 microg/ml). In conclusion, Rhei Rhizoma extract, which is taken orally at doses of 0.5-1 g each or 1-3 g daily in clinical practice, may cause pharmacokinetic herb-drug interactions in the process of the intestinal and/or hepatic CYP3A-mediated drug metabolism and P-glycoprotein- and/or MRP2-mediated efflux transport in the intestine.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hiroshima International University, Hiroshima, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yokooji
authors.forename: M
authors.initials: M
authors.lastname: Kida
authors.forename: M
authors.initials: M
authors.lastname: Mori
authors.forename: H
authors.initials: H
authors.lastname: Akashi
authors.forename: N
authors.initials: N
authors.lastname: Mori
authors.forename: S
authors.initials: S
authors.lastname: Yoshihara
authors.forename: T
authors.initials: T
authors.lastname: Murakami
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D016572:Cyclosporine / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004137:Dinitrochlorobenzene / Q000378:metabolism; D018757:GABA Modulators / Q000493:pharmacokinetics; D005978:Glutathione / Q000031:analogs & derivatives / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007202:Indicators and Reagents; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008874:Midazolam / Q000493:pharmacokinetics; D010936:Plant Extracts / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012250:Rheum / Q000737:chemistry*; D020112:Rhodamine 123
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D002352:Carrier Proteins; D004137:Dinitrochlorobenzene; D018757:GABA Modulators; D007166:Immunosuppressive Agents; D007202:Indicators and Reagents; D010936:Plant Extracts; D020112:Rhodamine 123; C030190:S-(2,4-dinitrophenyl)glutathione; D016572:Cyclosporine; D051544:Cytochrome P-450 CYP3A; D005978:Glutathione; D008874:Midazolam