TY - JOUR
T1 - Evidence on Integrating Pharmacokinetics to Find Truly Therapeutic Agent for Alzheimer's Disease
T2 - Comparative Pharmacokinetics and Disposition Kinetics Profiles of Stereoisomers Isorhynchophylline and Rhynchophylline in Rats
AU - Zhang, Chunyuan
AU - Wu, Xu
AU - Xian, Yanfang
AU - Zhu, Lin
AU - Lin, Ge
AU - Lin, Zhi-Xiu
AU - Ai, Yong
N1 - Funding Information:
This study was supported by a General Research Fund of the University Grants Council of Hong Kong SAR (Project no. 14110814).
Publisher Copyright:
© 2019 Chunyuan Zhang et al.
PY - 2019
Y1 - 2019
N2 - Isorhynchophylline (IRN) and rhynchophylline (RN), a pair of stereoisomers, are tetracyclic oxindole alkaloids isolated from Uncaria rhynchophylla, a commonly used Chinese medicinal herb. These two compounds have drawn extensive attention due to their potent neuroprotective effects with promising therapeutic potential for the treatment of Alzheimer's disease (AD). However, IRN and RN can interconvert into each other in vivo after oral administration. The present study aimed to elucidate the pharmacokinetic profiles and disposition kinetics of the administered and generated stereoisomers in the brain and cerebrospinal fluid (CSF) after oral administration of equal dose of IRN or RN to rats. Our study demonstrated that after oral administration, RN showed significantly higher systemic exposure (6.5 folds of IRN, p < 0.001) and disposition in the brain (2.5 folds of IRN, p < 0.01) and CSF (3 folds of IRN, p < 0.001) than IRN. The results indicated that interconversion between IRN and RN occurred. Notably, regardless of the orally administered IRN or RN, RN would always be one of the major or predominant forms present in the body. Our results provided sound evidence supporting further development of RN as a potential therapeutic agent for the treatment of AD. Moreover, the present study sets a solid example that integrating pharmacokinetics is crucial to identify the truly therapeutic agent.
AB - Isorhynchophylline (IRN) and rhynchophylline (RN), a pair of stereoisomers, are tetracyclic oxindole alkaloids isolated from Uncaria rhynchophylla, a commonly used Chinese medicinal herb. These two compounds have drawn extensive attention due to their potent neuroprotective effects with promising therapeutic potential for the treatment of Alzheimer's disease (AD). However, IRN and RN can interconvert into each other in vivo after oral administration. The present study aimed to elucidate the pharmacokinetic profiles and disposition kinetics of the administered and generated stereoisomers in the brain and cerebrospinal fluid (CSF) after oral administration of equal dose of IRN or RN to rats. Our study demonstrated that after oral administration, RN showed significantly higher systemic exposure (6.5 folds of IRN, p < 0.001) and disposition in the brain (2.5 folds of IRN, p < 0.01) and CSF (3 folds of IRN, p < 0.001) than IRN. The results indicated that interconversion between IRN and RN occurred. Notably, regardless of the orally administered IRN or RN, RN would always be one of the major or predominant forms present in the body. Our results provided sound evidence supporting further development of RN as a potential therapeutic agent for the treatment of AD. Moreover, the present study sets a solid example that integrating pharmacokinetics is crucial to identify the truly therapeutic agent.
UR - http://www.scopus.com/inward/record.url?scp=85062351693&partnerID=8YFLogxK
U2 - 10.1155/2019/4016323
DO - 10.1155/2019/4016323
M3 - Journal article
AN - SCOPUS:85062351693
SN - 1741-427X
VL - 2019
JO - Evidence-based Complementary and Alternative Medicine
JF - Evidence-based Complementary and Alternative Medicine
M1 - 4016323
ER -