Abstract
Koumine (KM), the most abundant alkaloid in Gelsemium elegans, has anti-neuropathic, anti-inflammatory, and analgesic activities; thus, it has the potential to be developed as a broad-spectrum analgesic drug. However, factors determining the relationship between analgesic efficacy and the corresponding plasma KM concentration are largely unclear. The pharmacokinetics and pharmacodynamics of KM and their optimization in the context of neuropathic pain have not been reported. We investigated the pharmacokinetics and pharmacodynamics of KM after oral administration in a streptozotocin-induced rat model of diabetic neuropathic pain (DNP) using a population approach. A first-order absorption and elimination pharmacokinetics model best described the plasma KM concentration. This pharmacokinetic model was then linked to a linear pharmacodynamic model with an effect compartment based on the measurement of the mechanical withdrawal threshold. KM was rapidly absorbed (time to maximum plasma concentration: 0.14–0.36 h) with similar values in both DNP and naïve rats, suggesting that DNP did not influence the KM absorption rate. However, the area under the curve (AUC0–∞) of KM in DNP rats was over 3-fold higher than that in naïve rats. The systemic clearance rate and volume of KM distribution were significantly lower in DNP rats than in naïve rats. Blood glucose value prior to KM treatment was a significant covariate for the systemic clearance rate of KM and baseline value of the threshold. Our results suggest that streptozotocin-induced hyperglycemia is an independent factor for decreased KM elimination and its anti-allodynic effects in a DNP rat model. To the best of our knowledge, this is the first study to investigate the role of DNP in the pharmacokinetics and pharmacokinetics-pharmacodynamics of KM in streptozotocin-induced diabetic rats.
Highlights
Diabetic neuropathic pain (DNP) is a chronic pain resulting from a lesion or disease of the nervous system after prolonged hyperglycemia, and is commonly characterized by a burning sensation and tactile allodynia (Gordois et al, 2003; Feldman et al, 2019)
STZ-Induced Diabetic Rats had Hyperglycemia, Tactile Allodynia, and Weight Loss Compared with Naïve Rats
Each dose of orally administered KM (0.28, 1.4, and 7.0 mg kg−1) significantly increased the mechanical withdrawal threshold (MWT) compared with the vehicle treatment in STZ-induced DNP rats
Summary
Diabetic neuropathic pain (DNP) is a chronic pain resulting from a lesion or disease of the nervous system after prolonged hyperglycemia, and is commonly characterized by a burning sensation and tactile allodynia (pain due to a normally nonnoxious stimuli) (Gordois et al, 2003; Feldman et al, 2019). As the most abundant alkaloid in Gelsemium elegans Benth., koumine (KM) has been demonstrated to effectively improve the mechanical withdrawal threshold (MWT) in streptozotocin (STZ)-treated rat models and to have a low toxicity. This indicates that KM may be a candidate for the treatment of DNP (Ling et al, 2014). The PK and PD of KM and their optimization in the context of neuropathic pain have not been reported
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
