title: Furanocoumarin derivatives in Kampo extract medicines inhibit cytochrome P450 3A4 and P-glycoprotein.
abstract: Furanocoumarins in grapefruit are known to show inhibitory effects against P-glycoprotein (P-gp) and CYP3A4 in intestinal epithelial cells; however, furanocoumarin derivatives are widely contained in the plants of Rutaceae and Umbelliferae families, which are used as components of Kampo extract medicines. In this study, we investigated the inhibitory effects of 12 furanocoumarins extracted from plants in the Umbelliferae family against P-gp and CYP3A4 activity. Furthermore, we studied their inhibitory effect on P-gp when furanocoumarins are used as Kampo extract medicine rather than as an isolated single compound. From screening of the CYP3A4 inhibitory effect, notopterol and rivulobirin A, the only dimer types of furanocoumarin, were found to be potent inhibitors of CYP3A4. On the other hand, byakangelicol and rivulobirin A showed strong P-gp inhibition from the screening of P-gp inhibitor evaluated by quinidine permeation through the Caco-2 monolayer; however, the chemical structural relationship of furanocoumarins between P-gp and CYP3A4 inhibitory effects could not be obtained. We also investigated the effect of these furanocoumarins on the transport of digoxin through the Caco-2 monolayer. The inhibitory effect of rivulobirin A was more potent than that of byakangelicol. Application of either Senkyu-cha-cho-san or Sokei-kakketsu-to, which are composed of herbal remedies in the Umbelliferae group, significantly decreased the efflux ratio of digoxin. In conclusion, it was found that some furanocoumarins extracted from the plants in the Umbelliferae family strongly inhibited P-gp and CYP3A4. Kampo extract medicines containing herbal remedies belonging to the Umbelliferae family may cause a drug-drug interaction with P-gp or a CYP3A4 substrate drug.
authors.affiliation: Division of Pharmaceutics, Osaka University of Pharmaceutical Sciences, Takatsuki-city, Osaka, Japan. iwanaga@gly.oups.ac.jp
authors.forename: Kazunori
authors.initials: K
authors.lastname: Iwanaga
authors.forename: Manami
authors.initials: M
authors.lastname: Hayashi
authors.forename: Yukimi
authors.initials: Y
authors.lastname: Hamahata
authors.forename: Makoto
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Makio
authors.initials: M
authors.lastname: Shibano
authors.forename: Masahiko
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Kimiye
authors.initials: K
authors.lastname: Baba
authors.forename: Masawo
authors.initials: M
authors.lastname: Kakemi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000889:Anti-Arrhythmia Agents / Q000378:metabolism; D018938:Caco-2 Cells; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004077:Digoxin / Q000378:metabolism; D011564:Furocoumarins / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D020835:Medicine, Kampo; D008874:Midazolam / Q000031:analogs & derivatives / Q000378:metabolism; D011802:Quinidine / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000889:Anti-Arrhythmia Agents; D065692:Cytochrome P-450 CYP3A Inhibitors; D011564:Furocoumarins; D004077:Digoxin; C040081:1-hydroxymethylmidazolam; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D011802:Quinidine; D008874:Midazolam