title: In vivo to in vitro effects of six bioactive lignans of Wuzhi tablet (Schisandra sphenanthera extract) on the CYP3A/P-glycoprotein-mediated absorption and metabolism of tacrolimus.
abstract: We recently reported that Wuzhi tablet (WZ; Schisandra sphenanthera extract) can inhibit P-glycoprotein (P-gp)-mediated efflux and CYP3A-mediated metabolism of tacrolimus (FK506) and thus increase the blood concentrations of FK506. Major active lignans of WZ include schisandrin A, schisandrin B, schisandrin C, schisandrol A, schisandrol B, and schisantherin A. Whether and how these six lignans affect the pharmacokinetics of FK506 remains unclear. Therefore, this study aimed to investigate the effects of these lignans on the first-pass absorption and metabolism of FK506 and the involved mechanisms in vitro and in vivo. The results showed that whole-blood concentrations of FK506 were increased to different degrees following coadministration of the six lignans, respectively. Schisandrol B showed the strongest effect on the increase of the area under the concentration-time curve, the oral bioavailability, the gut processes affecting availability, and the hepatic availability of FK506. The reduction of intestinal first-pass effect contributed most to the increase in oral bioavailability of FK506 when coadministered with schisandrol B. In vitro transport experiment showed that schisandrin A, schisandrin B, and schisandrol B inhibited P-gp-mediated efflux of FK506. In vitro metabolism study showed that the inhibitory effect of these six lignans on FK506 metabolism was dose-dependent. In conclusion, the exposure of FK506 in rats was increased when coadministered with these lignans, and schisandrol B showed the strongest effect. Lignans of WZ inhibited P-gp-mediated efflux and CYP3A-mediated metabolism of FK506, and the reduction of intestinal first-pass affected by the lignans was the major cause of the increased FK506 oral bioavailability.
authors.affiliation: School of Pharmaceutical Sciences (X.L.Q., X.P.X., Y.W., J.L.L, X.D.W., G.P.Z., M.H., H.C.B.) and The First Affiliated Hospital (X.C., C.X.W.), Sun Yat-sen University, Guangzhou, China; Department of Pharmacy, Pan Yu Central Hospital, Guangzhou, China (X.L.Q., H.Y.) and Department of Pharmacy, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China (Y.W., [the third author]).
authors.forename: Xiao Ling
authors.initials: XL
authors.lastname: Qin
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Xin Ping
authors.initials: XP
authors.lastname: Xue
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Jia Li
authors.initials: JL
authors.lastname: Li
authors.forename: Xue Ding
authors.initials: XD
authors.lastname: Wang
authors.forename: Guo Ping
authors.initials: GP
authors.lastname: Zhong
authors.forename: Chang Xi
authors.initials: CX
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.forename: Min
authors.initials: M
authors.lastname: Huang
authors.forename: Hui Chang
authors.initials: HC
authors.lastname: Bi
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism*; D000042:Absorption; D000818:Animals; D001682:Biological Availability; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D034242:Cyclooctanes / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004149:Dioxoles / Q000494:pharmacology; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D011083:Polycyclic Compounds / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013607:Tablets / Q000494:pharmacology*; D016559:Tacrolimus / Q000493:pharmacokinetics*
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D034242:Cyclooctanes; D004149:Dioxoles; D004365:Drugs, Chinese Herbal; D017705:Lignans; D011083:Polycyclic Compounds; D013607:Tablets; C520474:schisandrol A; C582515:wuzhi; C015499:schizandrin B; C033585:schizandrol B; C034734:schizandrin A; C034557:schizandrer A; C031409:schizandrin C; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus