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

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 (C max) 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 C max (T max) 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 (t 1/2) 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 t 1/2 of 1.4 and 7 mg•kg −1 KM were 1.5~2fold 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 C max in aged rats was higher than in adult rats during the T max period (P < 0.05). In aged rats, the AUC for KM was >2.5-fold higher (P < 0.05) and the t 1/2 was >60% longer than in adult rats (P < 0.05). These results help interpret the pharmacokinetics of KM in aging-associated diseases.

Streptozotocin-Induced Hyperglycemia Affects the Pharmacokinetics of Koumine and its Anti-Allodynic Action in a Rat Model of Diabetic Neuropathic Pain

“…The PK parameters calculated using the non-compartmental model are summarized in Table 1 . In accordance with our previously published studies ( Ye et al, 2020 ), the absorption of KM in the gastrointestinal tract was rapid (T max : 0.21–0.36 h) for all doses in DNP rats. KM was detected at 0.083 h in the majority of DNP rats.…”

“…Recently, we developed a sensitive UPLC-MS/MS method that requires only 50 μL of plasma to determine KM concentration, which was successfully utilized in a PK study in aged rats ( Ye et al, 2020 ). The results of method validation presented in Supplementary Figure S1 and Supplementary Tables S2–S4 were consistent with those of our previous study, suggesting that the concentrations of KM detected in the plasma are reliable.…”

“…The preparation and quantification of KM in the plasma were performed as previously reported ( Ye et al, 2020 ). In brief, 50 μL of plasma was spiked with GM at a final concentration of 80 ng ml −1 and evaporated to dryness.…”

“…Systemic clearance (CL) was calculated as dose/AUC 0-∞ . The apparent volume of distribution (V d ) was determined as CL/(slope of the terminal log-linear phase) ( Kim and Baek, 2018 ; Ye et al, 2020 ).…”

“…Our pervious study showed that KM-mediated analgesia may involve the activation of translocator protein (18 kDa), inhibition of spinal neuroinflammation, and enhancement of autophagy ( Xiong et al, 2017 ; Jin et al, 2018 ). Orally administered KM is rapidly absorbed (time to the maximum plasma concentration: 0.23–0.46 h) and has a short half-life (t 1/2 ) of 0.78–1.60 h in rats ( Wang et al, 2018a ; Wang et al, 2018b ; Su et al, 2020 ; Ye et al, 2020 ). Considering the possibility of drug-disease interactions when KM is used to treat DNP, it is important to understand the relation between DNP relief and the PK and PD of KM.…”