6β-纳曲醇单次和连续肌内注射给药在犬体内的药代动力学

研究6β-纳曲醇单次和连续肌内注射给药在犬体内的药代动力学。Beagle犬 (n = 4) 肌内注射6β-纳  曲醇0.2 mg·kg^?1, 每日1次, 连续7日。用反相高效液相-电化学检测法测定血浆6β-纳曲醇浓度。Beagle犬单次 (第一次) 及连续给药 (最后一次) 后的血药浓度经时变化过程均符合血管外给药一级吸收二室模型 (R² > 0.999), 药代动力学参数分别为t_1/2α (0.26 ± 0.23) 和 (0.19 ± 0.18) h, t_1/2β (4.77 ± 1.65) 和 (5.79 ± 1.50) h, C_max (81.65 ± 5.61) 和 (79.82 ± 10.5) ng·mL^?1, t_peak (0.27 ± 0.07) 和 (0.18 ± 0.08) h, CL_s (1.20 ± 0.06) 和 (1.12 ± 0.07) L·kg^?1·h^?1, V/F_c (1.94 ± 0.15) 和 (2.10 ± 0.27) L·kg^?1, AUC_0?t (166.82 ± 7.68) 和 (173.23 ± 9.49) ng·h·mL^?1。第一次和最后一次给药的药代动力学参数无显著性差异 (P > 0.05)。连续给药期间, 血药峰浓度和谷浓度的平均值分别为  (79.03 ± 10.3) 和 (1.50 ± 0.93) ng·mL^?1。结果显示, 6β-纳曲醇在犬体内的药物代谢过程符合一级吸收二室模型, 得到了相应的药代动力学参数; 连续给药对原形药物代谢过程基本无影响。

Pharmacokinetics of 6β-naltrexol after single and multiple intramuscular injections in Beagle dogs

The pharmacokinetics of 6β-naltrexol (6β-NOL) following single intramuscular administration and multiple intramuscular injection once per day for seven days was studied in 4 Beagle dogs.  Plasma   concentration of 6β-NOL in dogs was analyzed by a combination of high performance liquid chromatography (HPLC) and electrochemical detection with naloxone (NLX) as internal standard.  After single intramuscular injection of 0.2 mg·kg⁻¹ 6β-NOL, the plasma concentration-time curve of the drug was found to fit to a two   compartment model with first-order absorption.  The main parameters of single dosing were as follows: t_1/2α was (0.26 ± 0.23) h, t_1/2β was (4.77 ± 1.65) h, C_max was (81.65 ± 5.61) ng·mL⁻¹, t_peak was (0.27 ± 0.07) h, CL_s was (1.20 ± 0.06) L·kg⁻¹·h⁻¹, V/F_c was (1.94 ± 0.15) L·kg⁻¹, and AUC_0−t was (166.82 ± 7.68) ng·h·mL⁻¹, separately.  After multiple intramuscular injection of 0.2 mg·kg⁻¹ 6β-NOL once per day for seven days, the plasma      concentration-time curve of the drug fitted to a two compartment model with first-order absorption too.  The main parameters of the last dosing were as follows: t_1/2α was (0.19 ± 0.18) h, t_1/2β was (5.79 ± 1.50) h, C_max was (79.82 ± 10.5) ng·mL⁻¹, t_peak was (0.18 ± 0.08) h, CL_s was (1.12 ± 0.07) L·kg⁻¹·h⁻¹, V/F_c was (2.10 ± 0.27) L·kg⁻¹, and AUC_0−t was (173.23 ± 9.49) ng·h·mL⁻¹, separately.  The difference of the parameters between the first and the last dosing was not significant, showing that the plasma kinetics of 6β-naltrexol was not changed after  multiple administrations.  In the course of multiple administration, the peak and valley concentration of plasma 6β-naltrexol were (79.03 ± 10.3) and (1.50 ± 0.93) ng·mL⁻¹, respectively.  No clear adverse events were noted during this study.  These results showed that plasma 6β-naltrexol fits to a two compartment model with first-order absorption in dog after intramuscular administration and their pharmacokinetic parameters were   reported.  There was no remarkable change on plasma pharmacokinetics of 6β-naltrexol after multiple   intramuscular administrations.