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. 2020 Jul 21:11:1113.
doi: 10.3389/fphar.2020.01113. eCollection 2020.

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

Li-Xiang Ye  1 , Ying Xu  2 , Shui-Hua Zhang  1 , Da-Xuan Cao  1 , Ling-Fan Chen  1 , Yan-Ping Su  2 , Hui-Hui Huang  2 , Chang-Xi Yu  2   3   4
Affiliations

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

Li-Xiang Ye et al. Front Pharmacol. .

Abstract

Aging leads to changes in nearly all pharmacokinetic phases. Koumine (KM), an alkaloid derived from Gelsemium elegans 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 (Cmax) of 7 mg·kg-1 KM was ~12-fold and ~24-fold higher than that of 0.28 mg·kg-1 KM in adult and aged rats, respectively (P < 0.01). Time to reach Cmax (Tmax) for 7 mg·kg-1 KM was 4-fold longer in aged rats (P < 0.05). The area under the curve (AUC) of 7 mg·kg-1 KM was >17-fold and >43-fold higher than those of 0.28 mg·kg-1 KM in adult and aged rats, respectively (P < 0.01). The half-life (t1/2) of 7 mg·kg-1 KM was over 4-fold longer than that of 0.28 mg·kg-1 KM in adult rats (P < 0.01). The t1/2 of 1.4 and 7 mg·kg-1 KM were 1.5~2-fold longer, than that of 0.28 mg·kg-1 KM in aged rats (P < 0.05). The clearance rate of 7 mg·kg-1 KM was significantly lower in aged than in adult rats (P < 0.05). For 7.0 mg·kg-1 KM, the Cmax in aged rats was higher than in adult rats during the Tmax period (P < 0.05). In aged rats, the AUC for KM was >2.5-fold higher (P < 0.05) and the t1/2 was >60% longer than in adult rats (P < 0.05). These results help interpret the pharmacokinetics of KM in aging-associated diseases.

Keywords: Koumine; aging; dose proportionality; pharmacokinetics; ultra-performance liquid chromatography-tandem mass spectrometry.

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Figures

Figure 1
Figure 1
The chemical structures and full-scan precursor ions and products of Koumine (KM) (A) and internal standard (IS) (B).
Figure 2
Figure 2
Representative chromatograms of (A) blank rat plasma; (B) blank rat plasma spiked with Koumine (KM) (final concentration: 2.0 ng·ml−1), and internal standard (IS) (final concentration: 80 ng·ml−1); (C) adult rat plasma collected 0.17 h after a single intragastric administration of 1.4 mg·kg−1 KM; and (D) aged rat plasma collected 0.17 h after a single intragastric administration of 1.4 mg·kg−1 KM.
Figure 3
Figure 3
Plasma concentration-time profiles of Koumine (KM) following intragastric administration of (A) 0.28 mg·kg−1; (B) 1.4 mg·kg−1; and (C) 7.0 mg·kg−1 KM. Data are presented as the mean ± standard deviation (n = 6).
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