title: Inhibitory effects of furanocoumarin derivatives in Kampo extract medicines on P-glycoprotein at the blood-brain barrier.
abstract: Furanocoumarin derivatives, known as components of grapefruit juice, showing inhibitory effects against P-glycoprotein (P-gp) in the intestine are also 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 byakangelicol and rivulobirin A, known as furanocoumarins showing P-gp inhibitory effect using Caco-2 monolayer, against P-gp at the blood-brain barrier (BBB) under both in vitro and in vivo conditions. First we studied the membrane permeability of furanocoumarins to clarify whether they can be absorbed from the intestine. Both furanocoumarins showed high permeability through the Caco-2 monolayer, suggesting that they can easily reach the systemic circulation after oral administration. Then, we evaluated the effect of these furanocoumarins on the uptake of calcein acetoxymethyl ester (calcein-AM), a P-gp substrate, into bovine brain microvascular endothelial cells (BBMEC). Both furanocoumarins significantly increased the uptake amount of calcein-AM into BBMEC by the inhibition of P-gp at the BBB in vitro. Next we also investigated the P-gp inhibitory effect of these furanocoumarins at the rat BBB in vivo using verapamil as a P-gp substrate. Both furanocoumarins increased the B/P ratio of verapamil compared to the control, even under in vivo conditions; however, the extent of the inhibitory effect was much lower than in vitro condition. In conclusion, byakangelicol and rivulobirin A may inhibit P-gp expressed at the BBB even under in vivo conditions. Further studies using Kampo extract medicines under in vivo condition are necessary for safe drug therapy.
authors.affiliation: Division of Pharmaceutics, Osaka University of Pharmaceutical Sciences, Japan. iwanaga@gly.oups.ac.jp
authors.forename: Kazunori
authors.initials: K
authors.lastname: Iwanaga
authors.forename: Shinji
authors.initials: S
authors.lastname: Yoneda
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*; D000818:Animals; D019661:Apiaceae / Q000737:chemistry; D001692:Biological Transport / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018938:Caco-2 Cells; D002417:Cattle; D032083:Citrus paradisi / Q000737:chemistry; D003374:Coumarins / Q000493:pharmacokinetics / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D005452:Fluoresceins / Q000378:metabolism; D005663:Furans / Q000493:pharmacokinetics / Q000494:pharmacology*; D011564:Furocoumarins / Q000493:pharmacokinetics / Q000494:pharmacology*; D041743:Herb-Drug Interactions; D006801:Humans; D007408:Intestinal Absorption; D008297:Male; D020835:Medicine, Kampo; D010539:Permeability; D010936:Plant Extracts / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D027821:Rutaceae / Q000737:chemistry; D014700:Verapamil / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003374:Coumarins; D004791:Enzyme Inhibitors; D005452:Fluoresceins; D005663:Furans; D011564:Furocoumarins; D010936:Plant Extracts; C570292:rivulobirin A; C085925:calcein AM; C462034:byakangelicol; D014700:Verapamil