Differences of first-pass effect in the liver and intestine contribute to the stereoselective pharmacokinetics of rhynchophylline and isorhynchophylline epimers in rats

Wang, Xin; Zheng, Ming; Liu, Jia; Huang, Zhifeng; Bai, Yidan; Ren, Zhuoying; Wang, Ziwen; Tian, Yuwei; Zhou, Qiao; Liu, Wenyuan; Feng, Feng

doi:10.1016/j.jep.2017.07.039

Cited by 26 publications

(19 citation statements)

References 25 publications

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“…Both IRN and RN could pass through brain endothelial cells, while IRN showed a 1-fold higher BBB permeability than RN [33]. Additionally, the membrane permeability of RN was affected by P-gp efflux transporter [27, 34]. Overall, our study for the first time confirmed the in vivo BBB permeability of IRN and RN, with IRN more permeable than RN.…”

Section: Discussionsupporting

confidence: 64%

“…IRN was much more favorable to be metabolized than RN in the rat liver microsomes, and this stereo selectivity in hepatic metabolism of two stereoisomers was mainly mediated by CYP3A4 [28]. Moreover, the favorable conversion of IRN to RN also accounted for the low bioavailability of IRN [27]. The epimerization ratio of IRN to RN was 47.54 ± 0.22% in plasma while the epimerization ratio of RN to IRN is only 2.20 ± 0.04%.…”

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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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

Zhang

Xian

et al. 2019

Evidence-Based Complementary and Alternative Medicine

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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.

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

Zhang

Xian

et al. 2019

Evidence-Based Complementary and Alternative Medicine

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“…Degradation of the ECM promoted VSMC migration from the media of arterial walls to the intimal space, where VSMCs secreted more ECM products, progressively resulting in restenosis and neointima formation [40, 41]. Moreover, several migration regulatory proteins, including cell adhesion molecules ICAM-1, VCAM-1 [27, 42], MMP2, and MMP-9 were reported to be vital regulators of abnormal VSMC migration [43-45]. In the present study, our results indicated that atorvastatin calcium inhibited the expression of ICAM-1, VCAM-1, MMP2, and MMP-9 induced by PDGF-ββ stimulation.…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin Calcium Inhibits PDGF-ββ-Induced Proliferation and Migration of VSMCs Through the G0/G1 Cell Cycle Arrest and Suppression of Activated PDGFRβ-PI3K-Akt Signaling Cascade

Chen¹,

Dong²,

Zhao³

et al. 2017

Cell Physiol Biochem

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Background/Aims: Abnormal proliferation of vascular smooth muscle cells (VSMCs) is a hallmark of vascular lesions, such as atherosclerosis and restenosis. PDGF-ββ, an isoform of PDGF (platelet-derived growth factor), has been demonstrated to induce proliferation and migration of VSMCs. Atorvastatin calcium, a selective inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, has favorable protective effects on VSMCs. This study examined the effects of atorvastatin calcium on the proliferation and migration of PDGF-ββ-treated VSMCs, as well as its underlying mechanisms. Methods: MTT assays, Edu imaging, cell cycle analysis, wound healing assays, transwell migration assays, and western blot analysis were performed. Results: Atorvastatin calcium significantly inhibited cell proliferation, DNA synthesis and cell migration of PDGF-ββ-treated VSMCs. We demonstrated that atorvastatin calcium induced cell cycle arrest in the G0/G1 phase in response to PDGF-ββ stimulation and decreased the expression of G0/G1-specific regulatory proteins, including proliferating cell nuclear antigen (PCNA), CDK2, cyclin D1, cyclin E and CDK4 in PDGF-ββ-treated VSMCs. Moreover, pretreatment with atorvastatin calcium inhibited the PDGF-ββ-treated phosphorylation of PDGFRβ and Akt, whereas atorvastatin calcium did not affect the phosphorylation of PLC-γ1 or (ERK) 1/2. Conclusion: Our data suggested that atorvastatin calcium inhibited abnormal proliferation and migration of VSMCs through G0/G1 cell cycle arrest and suppression of the PDGFRβ-Akt signaling cascade.

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“…The predicted metabolic intrinsic clearance (CL′ int , ml/min/kg) of GL‐V9 in rats was calculated by Equation (Naritomi et al, ; Wang et al, ; Xiao et al, ).

CL'_{int} = \frac{0.693}{{normalT}_{1 / 2}} \times \frac{0.2 ml incubation volume}{0.2 mg / ml \times 0.2 ml microsomal protein} \times \frac{44.8 mg microsomal protein}{normalg liver weight} \times \frac{40 normalg liver weight}{kg body weight}

The prediction of hepatic bioavailability (F H ) in vivo was calculated based on the well‐stirred model as follows (Naritomi et al, )

F_{H} = \frac{{normalQ}_{normalH}}{Q_{H} + f_{B} \times \frac{true}{CL'_{int}}}

f_{B} = \frac{{normalf}_{normalu}}{{normalR}_{normalb}}

where f B is the unbound fraction in the whole blood, f u is the unbound fraction in plasma (0.45, obtained by the plasma protein binding experiment), f med determined as 1.0 is the unbound fraction in the microsome incubation system, Q H is the hepatic blood flow in rats, 55.2 ml/min/kg (Xiao et al, ).…”

Section: Methodsmentioning

confidence: 99%

Mechanistic study of absorption and first‐pass metabolism of GL‐V9, a derivative of wogonin

Xing

Ren

Kong

et al. 2019

Biopharm & Drug Disp

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GL-V9, a derivative of wogonin, has potent anti-cancer activity. The absorption and metabolism of this compound have not been investigated systematically. This study aims to illustrate the pharmacokinetic characters of GL-V9 by exploring its metabolic status under different administration routes. To further clarify the absorption mechanism of GL-V9, an in situ single-pass perfusion model and a Caco-2 cell monolayer model were used. Meanwhile, a microsomal incubation system was used to evaluate the enzyme kinetic parameters. In vivo, the obtained gastrointestinal availability (F a × F g ) was 21.28 ± 5.38%. The unmetabolized fraction in the gut wall (F gut wall ) was 98.59 ± 9.74%, while the hepatic bioavailability (F h ) was 29.11 ± 5.22%. These results indicated that poor absorption and extensive metabolism may contribute greatly to the low bioavailability of GL-V9. The effective permeability (P eff ) in the duodenum and jejunum was 1.34 ± 0.50 × 10 −4 and 0.90 ± 0.27 × 10 −4 cm/s, respectively. The high permeability of GL-V9 indicated that other unknown factors (such as metabolism) may account for its systemic exposure problem. Studies in rat liver microsomal (RLMs) confirmed this hypothesis, and the Cl int, CYP450s and UGT of GL-V9 was 0.20 ml/min/mg protein. In conclusion, these results suggest that GL-V9 possesses higher permeability than wogonin and the metabolism of GL-V9 is related to its disposition in rat intestine and liver.

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Differences of first-pass effect in the liver and intestine contribute to the stereoselective pharmacokinetics of rhynchophylline and isorhynchophylline epimers in rats

Cited by 26 publications

References 25 publications

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

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

Atorvastatin Calcium Inhibits PDGF-ββ-Induced Proliferation and Migration of VSMCs Through the G0/G1 Cell Cycle Arrest and Suppression of Activated PDGFRβ-PI3K-Akt Signaling Cascade

Mechanistic study of absorption and first‐pass metabolism of GL‐V9, a derivative of wogonin

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