Effects of P-glycoprotein on the intestine and blood-brain barrier transport of YZG-331, a promising sedative-hypnotic compound.
YZG-331 is a synthetic adenosine analogue which exhibits the sedative and hypnotic effects by binding to the adenosine receptor. The present study was designed to investigate the effects of P-glycoprotein (P-gp) on the intestine and brain distribution of YZG-331 in vitro and in vivo as well as related binding mechanisms. The activity of P-gp ATPase was both induced by YZG-331 and verapamil, a typical P-gp inhibitor, but affinity of YZG-331 for P-gp was lower than that of verapamil. The docking analyses further elucidated the binding relationship of YZG-331 and P-gp. The directional transport of YZG-331 was disappeared in Caco-2 and MDCK-MDR1 cells when the P-gp activity was blocked. However, the penetration of digoxin, a P-gp known substrate, was not change in MDCK-MDR1 cells along with YZG-331. In the everted intestinal sac model, the influx of YZG-331 was significantly reduced in the presence of verapamil in all the segments except for the colon. In the in situ and in vivo study, the brain exposure of YZG-331 was promoted after co-administered of verapamil. Furthermore, the Kp value changed from 0.03 to 0.05 after drug combination. Taken together, these results indicated that YZG-331 is a substrate but may not an inhibitor of P-gp. The intestine and brain permeability of YZG-331 can be restricted, at least in part, by P-gp. The drug interactions should be awarded when YZG-331 and other P-gp-related drugs used together.
Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, China. Electronic address: liuzhihao12399@126.com.
Zhihao
Z
Liu
Department of Drug Metabolism, Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: sylvia.mi@hotmail.com.
Jiaqi
J
Mi
Department of Drug Metabolism, Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: yangshuang@ouc.edu.cn.
Shuang
S
Yang
Department of Drug Metabolism, Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: zhaomanman@imm.ac.cn.
Manman
M
Zhao
Department of Drug Metabolism, Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: yanli@imm.ac.cn.
Yan
Y
Li
Department of Drug Metabolism, Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. Electronic address: shengli@imm.ac.cn.
Li
L
Sheng
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D004077:Digoxin / Q000378:metabolism; D004285:Dogs; D006801:Humans; D006993:Hypnotics and Sedatives / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D051379:Mice; D062105:Molecular Docking Simulation; D051381:Rats; D017207:Rats, Sprague-Dawley
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D006993:Hypnotics and Sedatives; C000589454:YZG-331; D004077:Digoxin; D000241:Adenosine
ATPase; Brain; Intestine; P-gp; YZG-331