Stereoselective glucuronidation metabolism, pharmacokinetics, anti-amnesic pharmacodynamics, and toxic properties of vasicine enantiomers in vitro and in vivo

Autor: Changhong Wang, Wei Liu, Hanxue Wang, Shenglan Qi, Xuemei Cheng, Shuping Li, Chao Ma, Yuwen Wang, Yunpeng Zhang, Gang Deng, Yongli Wang, Yudan Zhu
Rok vydání: 2018
Předmět:
0301 basic medicine
Male
Glucuronosyltransferase
Metabolic Clearance Rate
Metabolite
Guinea Pigs
Scopolamine
Glucuronidation
Pharmaceutical Science
Administration
Oral
Pharmacology
GPI-Linked Proteins
030226 pharmacology & pharmacy
Rats
Sprague-Dawley
03 medical and health sciences
chemistry.chemical_compound
Structure-Activity Relationship
0302 clinical medicine
Alkaloids
Glucuronides
Pharmacokinetics
Isomerism
Oral administration
Memory
Animals
Humans
Butyrylcholinesterase
Cholinesterase
biology
Behavior
Animal
Acetylcholinesterase
Metabolic Detoxication
Phase II
Mice
Inbred C57BL
Molecular Docking Simulation
Disease Models
Animal
030104 developmental biology
chemistry
UDP-Glucuronosyltransferase 1A9
biology.protein
Microsomes
Liver
Quinazolines
Administration
Intravenous
Female
Amnesia
Cholinesterase Inhibitors
Rabbits
Zdroj: European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. 123
ISSN: 1879-0720
Popis: Vasicine (VAS) is a potential natural cholinesterase inhibitor for treatment of Alzheimer's disease. Due to one chiral centre (C-3) presenting in molecule, VAS has two enantiomers, d-vasicine (d-VAS) and l-vasicine (l-VAS). The study was undertaken to investigate the stereoselective glucuronidation metabolism, pharmacokinetics, anti-amnesic effect and acute toxicity of VAS enantiomers. In results, the glucuronidation metabolic rate of l-VAS was faster than d-VAS in human liver microsomes and isoenzymes tests, and it was proved that the UDP-glucuronosyltransferase (UGT) 1A9 and UGT2B15 were the major metabolic enzymes for glucuronidation of l-VAS, while only UGT1A9 for d-VAS, which take responsibility of the significantly less metabolic affinity of d-VAS than l-VAS in HLM and rhUGT1A9. The plasma exposure of d-VAS in rats was 1.3-fold and 1.6-fold higher than that of l-VAS after intravenous and oral administration of d-VAS and l-VAS, respectively. And the plasma exposure of the major glucuronidation metabolite d-VASG was one of tenth of l-VASG or more less, no matter by intravenous or oral administration. Both d-VAS and l-VAS were exhibited promising acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities, and the BChE inhibitory activity of d-VAS with IC50 of 0.03 ± 0.001 μM was significantly stronger than that of l-VAS with IC50 of 0.98 ± 0.19 μM. The molecular docking results indicated that d-VAS and l-VAS could bind to the catalytic active site (CAS position) either of human AChE and BChE, and the BChE combing ability of d-VAS (the score of GBI/WAS dG -7.398) was stronger than that of l-VAS (the score of GBI/WAS dG -7.135). Both d-VAS and l-VAS could improving the learning and memory on scopolamine-induced memory deficits in mice. The content of acetylcholine (ACh) after oral administration d-VAS increased more than that of l-VAS in mice cortex, through inhibiting cholinesterase (ChE) and increasing choline acetyltransferase (ChAT). In addition, the LD50 value of d-VAS (282.51 mg·kg-1) was slight lower than l-VAS (319.75 mg·kg-1). These results indicated that VAS enantiomers displayed significantly stereoselective metabolic, pharmacokinetics, anti-amnesic effect and toxic properties in vitro and in vivo. The d-VAS might be the dominant configuration for treating Alzheimer's disease.
Databáze: OpenAIRE
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