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

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.

Oral Nanocurcumin Alone or in Combination with Insulin Alleviates STZ-Induced Diabetic Neuropathy in Rats

“…However, CUR undergoes extensive metabolism, leading to poor systemic bioavailability and limiting clinical translation . Our prior studies showed CUR acts on various molecular targets independent of glucose reduction in the STZ-induced diabetes model, , and nCUR (PLGA-GA 2 -CUR) produces a substantial increase in oral bioavailability in healthy rodents compared with the controls in the form of unformulated CUR, PLGA-CUR or PLGA-GA-CUR. ,, However, literature suggests that pathophysiology could affect the pharmacokinetics of the pharmaceutical drugs and this is more prominent with conventional dosage forms . Our prior studies have shown the bioavailability of unformulated CUR was significantly influenced compared to PLGA-CUR in a model of diet-induced metabolic syndrome; however, we did not measure CUR levels in the current study as the dose of unformulated CUR was 2 times higher than nCUR and because the blood was used for biochemistry and hematological parameters.…”

“…12,15,18 However, literature suggests that pathophysiology could affect the pharmacokinetics of the pharmaceutical drugs and this is more prominent with conventional dosage forms. 29 Our prior studies have shown the bioavailability of unformulated CUR was significantly influenced compared to PLGA-CUR in a model of diet-induced metabolic syndrome; 30 however, we did not measure CUR levels in the current study as the dose of unformulated CUR was 2 times higher than nCUR and because the blood was used for biochemistry and hematological parameters. On the other hand, empty particles do not have any therapeutic value and are deemed safe based on our prior studies with similar polymers and modifications.…”

Recent progress in chemistry and bioactivity of monoterpenoid indole alkaloids from the genus gelsemium : a comprehensive review

“…Its analgesic effects could be attributed to the modulation of spinal microglial M1 polarisation and proinflammatory mediators via inhibiting the Notch-RBP-Jκ signalling pathway 44 . Moreover, the study on pharmacokinetics indicated that koumine elimination was decreased in STZ-induced rats, suggesting koumine was retained for the treatment of DNP in vivo 45 . Gelsemine ( 3 ), is the principal active alkaloid from G. sempervirens .…”