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.
Highlights
Aging causes a decline in organ function and decreased efficacy of homeostatic systems, resulting in the alteration of most pharmacokinetic phases (Mangoni and Jackson, 2004)
To the best of our knowledge, this is the first report assessing the dose-dependent pharmacokinetics of KM following oral administration
We developed a sensitive UPLC-MS/MS method requiring a small volume of plasma to determine KM levels in a pharmacokinetic study involving adult and aged rats
Summary
Aging causes a decline in organ function and decreased efficacy of homeostatic systems, resulting in the alteration of most pharmacokinetic phases (Mangoni and Jackson, 2004). (G. elegans) has various pharmacological properties and is known to be effective in the treatment of numerous age-associated conditions including postoperative pain (Xiong et al, 2017; Shoaib et al, 2019), inflammation (Yuan et al, 2016; Wu et al, 2020), rheumatoid arthritis (Yang et al, 2016), malignant tumors (Yuan et al, 2019a), nonalcoholic fatty liver disease (Yue et al, 2019), oxidative stress (Yuan et al, 2019b), and neuropathic pain (Jin et al, 2018a; Jin et al, 2018b). The pharmacokinetic profile of KM in the elderly or aged animals remains to be fully evaluated
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