Journal of pharmacological and toxicological methods · 2026
Study on pharmacokinetic behaviors of colchicine sustained-release microspheres in beagle dogs and its relevance to toxicity mitigation via LC-MS/MS.
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Yang Chuyao, Wang Jingtao, Zhang Qiannan, Wang Yuli, Wang Lingchao, Zhang Wenpeng, Xu Jinghua, Zhuang Xiaomei
Аннотация
OBJECTIVE: This study aimed to develop a simple and highly sensitive LC-MS/MS (Liquid Chromatography-Tandem Mass Spectrometry) method for quantifying colchicine in beagle plasma and use it to investigate the pharmacokinetic (PK) characteristics of colchicine sustained-release microspheres (SRMs) in beagles.
METHODS: Plasma proteins were precipitated using methanol. Following centrifugation, the supernatant was vacuum-concentrated and reconstituted in 0.1% formic acid aqueous solution. Separation was performed on a Kromasil 100-5-C8 column (2.1 × 50 mm), with detection carried out via positive ion electrospray ionization (ESI) in multiple reaction monitoring (MRM) mode. A total of 12 beagles (9 males, 3 females) were enrolled in two crossover pharmacokinetic studies with washout periods of 3 weeks, respectively. Single-dose studies (6 males, 4-treatment, 4-period) included intravenous colchicine API (1 μg/kg), oral SRMs (0.25/0.5 mg) and commercial tablets (0.5 mg); multiple-dose studies (3 males/3 females, 2-treatment, 2-period) involved daily oral gavage of 0.5 mg SRMs or tablets for 5 consecutive days.
RESULTS: The method exhibited good linearity (r2 > 0.990, 0.025-50 ng/mL), with qualified precision, accuracy, extraction recovery, matrix effects and stability. Colchicine had moderate clearance (CL, 0.98 ± 0.18 L/h/kg) and extensive volume of distribution (Vz, 1.27 ± 0.24 L/kg). Compared with isodose tablets, single-dose SRMs had lower Cₘₐₓ (8.27 ± 2.64 vs 2.81 ± 0.24 ng/mL) and prolonged Tₘₐₓ [1.0 (0.88-1.25) vs 2.0 (2.0-2.5) h]. Both gropus of multiple-dose PK showed no accumulation (accumulation factor, R < 1.2); colchicine SRMs exhibited a lower fluctuation index (FI, a key PK parameter calculated as the ratio Cmax/Cmin after repeated dosing) (30.04 ± 8.99 vs 50.07 ± 9.37, P < 0.01).
CONCLUSION: The developed LC-MS/MS method meets the requirements for colchicine SRMs pharmacokinetic studies in beagles. Compared with conventional tablets, colchicine SRMs offer improved safety and efficacy.
METHODS: Plasma proteins were precipitated using methanol. Following centrifugation, the supernatant was vacuum-concentrated and reconstituted in 0.1% formic acid aqueous solution. Separation was performed on a Kromasil 100-5-C8 column (2.1 × 50 mm), with detection carried out via positive ion electrospray ionization (ESI) in multiple reaction monitoring (MRM) mode. A total of 12 beagles (9 males, 3 females) were enrolled in two crossover pharmacokinetic studies with washout periods of 3 weeks, respectively. Single-dose studies (6 males, 4-treatment, 4-period) included intravenous colchicine API (1 μg/kg), oral SRMs (0.25/0.5 mg) and commercial tablets (0.5 mg); multiple-dose studies (3 males/3 females, 2-treatment, 2-period) involved daily oral gavage of 0.5 mg SRMs or tablets for 5 consecutive days.
RESULTS: The method exhibited good linearity (r2 > 0.990, 0.025-50 ng/mL), with qualified precision, accuracy, extraction recovery, matrix effects and stability. Colchicine had moderate clearance (CL, 0.98 ± 0.18 L/h/kg) and extensive volume of distribution (Vz, 1.27 ± 0.24 L/kg). Compared with isodose tablets, single-dose SRMs had lower Cₘₐₓ (8.27 ± 2.64 vs 2.81 ± 0.24 ng/mL) and prolonged Tₘₐₓ [1.0 (0.88-1.25) vs 2.0 (2.0-2.5) h]. Both gropus of multiple-dose PK showed no accumulation (accumulation factor, R < 1.2); colchicine SRMs exhibited a lower fluctuation index (FI, a key PK parameter calculated as the ratio Cmax/Cmin after repeated dosing) (30.04 ± 8.99 vs 50.07 ± 9.37, P < 0.01).
CONCLUSION: The developed LC-MS/MS method meets the requirements for colchicine SRMs pharmacokinetic studies in beagles. Compared with conventional tablets, colchicine SRMs offer improved safety and efficacy.