Evidence on Integrating Pharmacokinetics to Find Truly Therapeutic Agent for Alzheimer’s Disease: Comparative Pharmacokinetics and Disposition Kinetics Profiles of Stereoisomers Isorhynchophylline and Rhynchophylline in Rats

Hindawi Evidence-Based Complementary and Alternative Medicine Volume 2019, Article ID 4016323, 9 pages https://doi.org/10.1155/2019/4016323 Research Article Evidence on Integrating Pharmacokinetics to Find Truly Therapeutic Agent for Alzheimer’s Disease: Comparative Pharmacokinetics and Disposition Kinetics Profiles of Stereoisomers Isorhynchophylline and Rhynchophylline in Rats Chunyuan Zhang ,1 Xu Wu,1,2 Yanfang Xian,1 Lin Zhu,3 Ge Lin ,3 and Zhi-Xiu Lin 1 1 School of Chinese Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou 646000, Sichuan, China 3 School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong 2 Correspondence should be addressed to Ge Lin; and Zhi-Xiu Lin; Chunyuan Zhang and Xu Wu contributed equally to this work. Received 27 September 2018; Revised 4 December 2018; Accepted 9 January 2019; Published 3 February 2019 Guest Editor: Yong Ai Copyright © 2019 Chunyuan Zhang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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. 1. Introduction Alzheimer’s disease (AD) is the most common form of neurodegenerative disease in the elderly population [1, 2]. Alkaloids-containing herbal extracts have been widely used as therapeutic agents in traditional medicine for thousands of years [3]. The use of naturally occurring alkaloids as therapeutic agents for AD treatment has drawn extensive attention, and the U.S. Food and Drug Administration has recently approved two alkaloids, i.e., galantamine and rivastigmine, which act as cholinesterase inhibitors, for the treatment of AD [4, 5]. Uncaria rhynchophylla (Gou-Teng in Chinese) has been demonstrated as a promising herbal medicine for the treatment of AD. The extract of U. rhynchophylla has been reported to have potent antiaggregation effects on amyloid𝛽 proteins [6] and was demonstrated to improve cognitive deficits induced by D-galactose in mice [7]. The major active components in U. rhynchophylla have been revealed to be oxindole alkaloids. Isorhynchophylline (IRN) and rhynchophylline (RN) (Figure 1) are tetracyclic oxindole alkaloids accounting for more than 43% of the total alkaloid content in U. rhynchophylla [8] and have been regarded as the major pharmacologically active components in the 2 Evidence-Based Complementary and Alternative Medicine 6 9 7 8 10 11 1 12 2 5 H N4 3 N O 15 H H3 CO 22 16 13 14 23 20 17 19 18 OCH3 N O H H3 CO O O IRN RN O H3 CO C H3 C H 21 N H N OCH3 NO2 C OCH3 O CH3 Nifedipine Figure 1: Chemical structures of isorhynchophylline (IRN), rhynchophylline (RN) and nifedipine (internal standard, IS). herb [9–11]. Investigations of the pharmacological effects of IRN and RN have revealed that they could exert beneficial effects on AD. Recent studies conducted by our group have indicated that IRN could rescue PC12 cells from amyloid𝛽-induced apoptosis [12] and also exhibited neuroprotective effect in amyloid-𝛽-treated PC12 cells [13]. Both IRN and RN were able to exert neuroprotective effect by protecting amyloid-𝛽-treated PC12 cells from cell death [14]. Furthermore, IRN could ameliorate cognitive deficits, enhance the antioxidative status, and reduce inflammation via inhibition of the NF-𝜅B signaling pathway in the brain tissues of the Dgalactose-induced mice [15]. IRN was also able to improve cognitive deficits via the inhibition of neuronal apoptosis and tau protein hyperphosphorylation in the hippocampus of the amyloid-𝛽-treated rats [16]. More recently, other research groups identified RN as an inhibitor of tyrosine kinase EphA4 receptor and demonstrated that RN could restore the synaptic impairment in the transgenic mouse models of AD [17] and could ameliorate amyloid-𝛽-induced perturbation of hippocampal CA1 neuronal activity [18]. Because both IRN and RN are promising candidates for further development into therapeutic agents for AD, understanding their disposition kinetics in the brain and cerebrospinal fluid (CSF) and plasma levels of IRN and RN is important. In addition, IRN and RN are a pair of stereoisomers at C7 chiral position. Interconversion between IRN and RN was firstly discovered by Wenkert et al. in 1959 [19], and this phenomenon has been observed both in vitro and in vivo [20–29]. It is worth noting that stereoconfiguration at C7 position of IRN and RN may lead to differences in their pharmacokinetics. Therefore, knowledge of the difference in pharmacokinetic profiles and disposition kinetics of IRN and RN and the epimerization between them is critical for further development of their therapeutic usage. However, previous pharmacokinetic studies on IRN and RN were only conducted separately [20–22]. The most recent stereoselective pharmacokinetic study on IRN and RN failed to reveal the disposition kinetics in the brain and the pharmacokinetic profiles of generated stereoisomers [27, 29]. In the present study, we aimed to elucidate the kinetic profiles of the orally administered and metabolically generated stereoisomers in the brain, CSF, and plasma of rats via studying in parallel both IRN and RN. 2. Materials and Methods 2.1. Chemicals and Reagents. IRN (purity ≥ 98%) and RN (purity ≥ 98%) were purchased from Chengdu Mansite Pharmaceutical Co. Ltd. (Chengdu, Sic (...truncated)