Effect of Tacrolimus on the pharmacokinetics of bioactive lignans of Wuzhi tablet (Schisandra sphenanthera extract) and the potential roles of CYP3A and P-gp.
We recently reported that Wuzhi tablet (WZ), a preparation of the ethanol extract of Wuweizi (Schisandra sphenanthera), had significant effects on blood concentrations of Tacrolimus (FK506) in renal transplant recipients and rats. The active lignans in WZ are schisandrin A, schisandrin B, schisandrin C, schisandrol A, schisandrol B, schisantherin A, and schisantherin B. Until now, whether the pharmacokinetics of these lignans in WZ would be affected by FK506 remained unknown. Therefore, this study aimed to investigate whether and how FK506 affected pharmacokinetics of lignans in WZ in rats and the potential roles of CYP3A and P-gp. After a single oral co-administration of FK506 and WZ, the blood concentration of lignans in WZ was decreased by FK506; furthermore, the AUC of schisantherin A, schisandrin A, schisandrol A and schisandrol B was only 64.5%, 47.2%, 55.1% and 57.4% of that of WZ alone group, respectively. Transport study in Caco-2 cells showed that these lignans were not substrates of P-gp, suggesting decreased blood concentration of lignans by FK506 was not via P-gp pathway. Metabolism study in the human recombinant CYP 3A showed that these lignans had higher affinity to CYP3A than that of FK506, and thus had a stronger CYP3A-mediated metabolism. It was concluded that the blood concentrations of these lignans were decreased and their CYP3A-mediated metabolisms were increased in the presence of FK506 since these lignans had higher affinity to CYP3A.
Laboratory of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China; Guangdong Food and Drug Vocational College, Guangzhou, China.
Xiao-ling
XL
Qin
The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. Electronic address: frankwychen@yahoo.com.
Xiao
X
Chen
Laboratory of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
Guo-ping
GP
Zhong
Laboratory of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
Xiao-mei
XM
Fan
Department of Pharmacy, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Ying
Y
Wang
Laboratory of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
Xin-ping
XP
Xue
Laboratory of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
Ying
Y
Wang
Laboratory of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
Min
M
Huang
Laboratory of Drug Metabolism and Pharmacokinetics, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China. Electronic address: bihchang@mail.sysu.edu.cn.
Hui-chang
HC
Bi
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D018938:Caco-2 Cells; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004347:Drug Interactions; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D017705:Lignans / Q000032:analysis / Q000493:pharmacokinetics*; D008297:Male; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D032141:Schisandra / Q000737:chemistry*; D016559:Tacrolimus / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004365:Drugs, Chinese Herbal; D007166:Immunosuppressive Agents; D017705:Lignans; C582515:wuzhi; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; D016559:Tacrolimus
Herb–drug interaction; Lignans; Pharmacokinetics; Schisandra sphenanthera extract; Tacrolimus; Wuzhi tablet