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Pharmacokinetic and Metabolomic Analysis of Randomized， Double-blind， Placebo-controlled，Continuous Administration of Fuqi Gubengao in Healthy Chinese Subjects

  • role： First author第一作者
  • Affiliation：

    Yunnan Province Company Key Laboratory for Traditional Chinese Medicine（TCM） and Ethnic Drug of New Drug Creation，Yunnan Institute of Materia Medica，Kunming 650111，China

  • Email：Biotljy@163.com
  • Introduction：刘峻宇，硕士，工程师，执业药师，从事新药临床研究，Tel：0871-68411189，E-mail：Biotljy@163.com
LIU Junyu1,  
  • Affiliation：

    Key Laboratory for Clinical Research and Evaluation of TCM of National Medical Products Administration，National Clinical Research Center for Chinese Medicine Cardiology， Xiyuan Hospital of China Academy of Chinese Medical Sciences，Beijing 100091，China

CAO Weiyi2,  
  • Affiliation：

    Yunnan Province Company Key Laboratory for Traditional Chinese Medicine（TCM） and Ethnic Drug of New Drug Creation，Yunnan Institute of Materia Medica，Kunming 650111，China

SUN Min1,  
  • Affiliation：

    Key Laboratory for Clinical Research and Evaluation of TCM of National Medical Products Administration，National Clinical Research Center for Chinese Medicine Cardiology， Xiyuan Hospital of China Academy of Chinese Medical Sciences，Beijing 100091，China

LU Fang2,  
  • Affiliation：

    Key Laboratory for Clinical Research and Evaluation of TCM of National Medical Products Administration，National Clinical Research Center for Chinese Medicine Cardiology， Xiyuan Hospital of China Academy of Chinese Medical Sciences，Beijing 100091，China

YANG Qiaoning2,  
  • Affiliation：

    Key Laboratory for Clinical Research and Evaluation of TCM of National Medical Products Administration，National Clinical Research Center for Chinese Medicine Cardiology， Xiyuan Hospital of China Academy of Chinese Medical Sciences，Beijing 100091，China

ZHANG Wantong2,  
  • Affiliation：

    Key Laboratory for Clinical Research and Evaluation of TCM of National Medical Products Administration，National Clinical Research Center for Chinese Medicine Cardiology， Xiyuan Hospital of China Academy of Chinese Medical Sciences，Beijing 100091，China

QU Hua2,  
  • Affiliation：

    Key Laboratory for Clinical Research and Evaluation of TCM of National Medical Products Administration，National Clinical Research Center for Chinese Medicine Cardiology， Xiyuan Hospital of China Academy of Chinese Medical Sciences，Beijing 100091，China

WANG Shuge2,  
  • role： Corresponding author通信作者
  • Affiliation：

    Key Laboratory for Clinical Research and Evaluation of TCM of National Medical Products Administration，National Clinical Research Center for Chinese Medicine Cardiology， Xiyuan Hospital of China Academy of Chinese Medical Sciences，Beijing 100091，China

  • Email：crystal005@163.com
  • Introduction：李睿，博士，主任医师，从事中医药临床疗效评价研究，Tel：010-62862428，E-mail：crystal005@163.com； *
LI Rui2*,  
  • role： Corresponding author通信作者
  • Affiliation：

    Key Laboratory for Clinical Research and Evaluation of TCM of National Medical Products Administration，National Clinical Research Center for Chinese Medicine Cardiology， Xiyuan Hospital of China Academy of Chinese Medical Sciences，Beijing 100091，China

  • Email：ruigao@126.com
  • Introduction：高蕊，博士，主任医师，从事中医药临床评价方法学研究，Tel：010-62835653，E-mail：ruigao@126.com
GAO Rui2*

resumen

ObjectiveTo evaluate the tolerance of healthy subjects to Fuqi Gubengao， and to explore the pharmacokinetics of its major active components and the potential mechanisms in treating syndrome of deficiency of kidney Yang.MethodA Single-center， randomized， double-blind， continuous administration， placebo-controlled trial was designed. A total of 24 healthy subjects were enrolled in 2 dosage groups（75 g and 100 g）， with each group consisting of 12 participants randomized in a ratio of 2∶1 to either the experimental and placebo groups， and each group was given the drug or the placebo at the dose for 14 d， the physical signs of subjects were recorded for safety assessment. Biological samples were collected at the specified time points according to the trial protocol. The concentrations of 6 aconite alkaloids（aconitine， mesaconitine， hypaconitine， benzoylaconine， benzoylmesaconine and benzoylhypacoitine） in the biological samples were determined using ultra-high performance liquid chromatography-triple quadrupole tandem mass spectrometry（UPLC-QqQ-MS/MS）， and pharmacokinetic parameters were calculated by non-compartment model. The relative contents of endogenous metabolites in plasma and urine samples were measured by UPLC-quadrupole-time-of-flight mass spectrometry（UPLC-Q-TOF-MS）. Principal component analysis（PCA）， partial least squares-discriminant analysis（PLS-DA） and orthogonal partial least squares-discriminant analysis（OPLS-DA） were performed by EZinfo 3.0 software， differential metabolites were screened with variable importance in the projection（VIP） value>1 and P<0.05， and pathway enrichment analysis was conducted using MetaboAnalyst 6.0 platform.ResultIn the safety evaluation， no trend of significant increase in adverse events with increasing dose was observed. Pharmacokinetic results showed that the plasma concentrations of aconitine， mesaconitine and hypaconitine were mostly below the limit of quantification， and 71% of the plasma concentration of benzoylaconine was below the limit of quantification after the initial administration. The plasma concentration of benzoylmesaconine in the 75 g and 100 g groups reached steady state after 12 d of continuous administration， and compared with the first administration， the concentration and overall exposure in the body increased after the last administration， but there was no safety-related drug accumulation. Forty-five differential metabolites induced by Fuqi Gubengao were identified in the plasma samples， including 11 acylcarnitines， 10 fatty acids， 4 amino acids， and 20 lipids， enriched in pathways such as α-linolenic and linoleic acid metabolism， branched-chain fatty acid oxidation， phenylalanine and tyrosine metabolism， and fatty acid biosynthesis. Twenty-two differential metabolites were identified in the urine， mainly including 7 amino acids and their metabolites， 7 nucleic acids and their metabolites， 2 carnitines， and 6 others， enriched in pathways such as tryptophan metabolism， pantothenic acid and coenzyme A（CoA） biosynthesis， β-alanine metabolism， and sphingolipid metabolism.ConclusionFuqi Gubengao shows good clinical safety and tolerability at the tested doses， its mechanism in treating kidney Yang deficiency may be related to enhancing adrenal function， promoting fat breakdown and oxidation， and enhancing energy metabolism in the body.

palabra clave

Fuqi Gubengao;phase Ⅰ clinical study;pharmacokinetics;metabolomics;safety;tolerability

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