Abstract
Sinomenine is a bioactive alkaloid isolated from the Chinese medicinal plant Sinomenium acutum (Thunb.) Rehd. et Wils which exhibits significant analgesic, anti-inflammatory, and immunosuppressive effects. Sinomenine hydrochloride (SH) preparations, classified as natural disease-modifying antirheumatic drugs, are currently available for the treatment of rheumatoid arthritis and other rheumatic diseases. Our toxicity evaluation demonstrated that the median lethal dose of SH in female Sprague-Dawley (SD) rats was over 11 times greater than that in male SD rats, revealing striking sex-linked differences in the safety profile of SH. The present study was designed to investigate differences in the pharmacokinetics (PKs) and tissue distribution of SH between male and female SD rats after a single oral dose of 25 mg/kg. PK and tissue distribution studies were performed using a validated UPLC-MS/MS method. The results showed that SH-treated SD female rats displayed markedly greater drug exposure, and SH exhibited a longer half-life and slower clearance rate than comparable studies in male rats. Moreover, the tissue distribution study confirmed that the sinomenine concentration in female rats was considerably greater in the internal organs than in male rats. Our study demonstrates, for the first time, significant sex-related differences in the safety profile and PKs of SH, which may be associated with a distinct sex-dependent metabolic mechanism of sinomenine.
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Abbreviations
- SH:
-
Sinomenine hydrochloride
- nDMARD:
-
Natural disease-modifying anti-rheumatic drug
- RA:
-
Rheumatoid arthritis
- LD50 :
-
Median lethal dose
- SD:
-
Sprague-Dawley
- PK:
-
Pharmacokinetic
- UPLC-MS/MS:
-
Ultra-high-performance liquid chromatography tandem mass spectrometry
- ZQFTN:
-
Zhengqing Fengtongning
- ADME:
-
Absorption, distribution, metabolism, and excretion/elimination
- IS:
-
Internal standard
- HNUCM:
-
Hunan University of Chinese Medicine
- NIH:
-
National Institute of Health
- QC:
-
Quality control
- ESI:
-
Electrospray ionization
- MRM:
-
Multiple-reaction monitoring
- LLOQ:
-
Lower limit of quantification
- S/N:
-
Signal-to-noise
- RE:
-
Relative error
- RSD:
-
Relative standard deviation
- ANOVA:
-
Analysis of variance
- LSD:
-
Least significant difference
- CYP450s:
-
Cytochrome P450
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Acknowledgements
This study was funded by grants from the National Natural Science Foundation of China General Program (8227153595), the Science and Technology Innovation Program of Hunan Province (2020SK1020 and XKJ[2021]43-2021RC4035) and was supported by the Hunan Furong Distinguished Scholar Program (XJT[2020]58), Hunan 121 Training Project for Innovative Talents (XRSH[2019]192), Chinese Academy of Engineering Academician Liang Liu’s Workstation of Hunan University of Chinese Medicine (HNUCM) (XKXT[2020]34), and the National First-class Disciple Construction Project of Chinese Medicine of HNUCM (XXKZ[2018]3).
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Huang, H., Zhang, EB., Yi, OY. et al. Sex-related differences in safety profiles, pharmacokinetics and tissue distribution of sinomenine hydrochloride in rats. Arch Toxicol 96, 3245–3255 (2022). https://doi.org/10.1007/s00204-022-03368-1
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DOI: https://doi.org/10.1007/s00204-022-03368-1