AUTHOR=Ye Li-Xiang , Xu Ying , Zhang Shui-Hua , Cao Da-Xuan , Chen Ling-Fan , Su Yan-Ping , Huang Hui-Hui , Yu Chang-Xi 

TITLE=Orally Administered Koumine Persists Longer in the Plasma of Aged Rats Than That of Adult Rats as Assessed by Ultra-Performance Liquid Chromatography-Tandem Mass Spectrometry

JOURNAL=Frontiers in Pharmacology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2020.01113

DOI=10.3389/fphar.2020.01113

ISSN=1663-9812

ABSTRACT=<p>Aging leads to changes in nearly all pharmacokinetic phases. Koumine (KM), an alkaloid derived from <italic>Gelsemium elegans</italic> Benth., is effective against age-associated chronic diseases, but its dose proportionality following oral administration in aged individuals remains unknown. Herein, we established and validated a simple method that requires low sample volumes to determine KM concentration in rats using ultra-performance liquid chromatography-tandem mass spectrometry. The maximum plasma concentration (C<sub>max</sub>) of 7 mg·kg<sup>−1</sup> KM was ~12-fold and ~24-fold higher than that of 0.28 mg·kg<sup>−1</sup> KM in adult and aged rats, respectively (<italic>P</italic> &lt; 0.01). Time to reach C<sub>max</sub> (T<sub>max</sub>) for 7 mg·kg<sup>−1</sup> KM was 4-fold longer in aged rats (<italic>P</italic> &lt; 0.05). The area under the curve (AUC) of 7 mg·kg<sup>−1</sup> KM was &gt;17-fold and &gt;43-fold higher than those of 0.28 mg·kg<sup>−1</sup> KM in adult and aged rats, respectively (<italic>P</italic> &lt; 0.01). The half-life (t<sub>1/2</sub>) of 7 mg·kg<sup>−1</sup> KM was over 4-fold longer than that of 0.28 mg·kg<sup>−1</sup> KM in adult rats (<italic>P</italic> &lt; 0.01). The t<sub>1/2</sub> of 1.4 and 7 mg·kg<sup>−1</sup> KM were 1.5~2-fold longer, than that of 0.28 mg·kg<sup>−1</sup> KM in aged rats (<italic>P</italic> &lt; 0.05). The clearance rate of 7 mg·kg<sup>−1</sup> KM was significantly lower in aged than in adult rats (<italic>P</italic> &lt; 0.05). For 7.0 mg·kg<sup>−1</sup> KM, the C<sub>max</sub> in aged rats was higher than in adult rats during the T<sub>max</sub> period (<italic>P</italic> &lt; 0.05). In aged rats, the AUC for KM was &gt;2.5-fold higher (<italic>P</italic> &lt; 0.05) and the t<sub>1/2</sub> was &gt;60% longer than in adult rats (<italic>P</italic> &lt; 0.05). These results help interpret the pharmacokinetics of KM in aging-associated diseases.</p>