Objective

To describe the pharmacokinetics and selected pharmacodynamic variables of codeine and its metabolites in Thoroughbred horses following a single oral administration.

Study design

Prospective experimental study.

Animals

A total of 12 Thoroughbred horses, nine geldings and three mares, aged 4–8 years.

Methods

Horses were administered codeine (0.6 mg kg^–1) orally and blood was collected before administration and at various times until 120 hours post administration. Plasma and urine samples were collected and analyzed for codeine and its metabolites by liquid chromatography–mass spectrometry, and plasma pharmacokinetics were determined. Heart rate and rhythm, step counts, packed cell volume and total plasma protein were measured before and 4 hours after administration.

Results

Codeine was rapidly converted to the metabolites norcodeine, codeine-6-glucuronide (C6G), morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Plasma codeine concentrations were best represented using a two-compartment model. The C_max, t_max and elimination t_½ were 270.7 ± 136.0 ng mL^–1, 0.438 ± 0.156 hours and 2.00 ± 0.534 hours, respectively. M3G was the main metabolite detected (C_max 492.7 ± 35.5 ng mL^–1), followed by C6G (C_max 96.1 ± 33.8 ng mL^–1) and M6G (C_max 22.3 ± 4.96 ng mL^–1). Morphine and norcodeine were the least abundant metabolites with C_max of 3.17 ± 0.95 and 1.42 ± 0.79 ng mL^–1, respectively. No significant adverse or excitatory effects were observed.

Conclusions and clinical relevance

Following oral administration, codeine is rapidly metabolized to morphine, M3G, M6G, C6G and norcodeine in horses. Plasma concentrations of M6G, a presumed active metabolite of morphine, were comparable to concentrations reported previously following administration of an analgesic dose of morphine to horses. Codeine was well tolerated based on pharmacodynamic variables and behavioral observations.

中文翻译：

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马单次口服后可待因的代谢、药代动力学和选定的药效学效应。

客观的

描述纯种马单次口服给药后可待因及其代谢物的药代动力学和选定的药效学变量。

学习规划

前瞻性实验研究。

动物

共有 12 匹纯种马，9 匹骟马和 3 匹母马，年龄为 4-8 岁。

方法

马口服可待因 (0.6 mg kg ^–1 )，并在给药前和给药后不同时间采集血液，直至给药后 120 小时。收集血浆和尿液样本，通过液相色谱-质谱法分析可待因及其代谢物，并测定血浆药代动力学。在给药前和给药后4小时测量心率和节律、步数、细胞堆积体积和总血浆蛋白。

结果

可待因迅速转化为代谢物去甲可待因、可待因-6-葡萄糖苷酸（C6G）、吗啡、吗啡-3-葡萄糖苷酸（M3G）和吗啡-6-葡萄糖苷酸（M6G）。使用两室模型可以最好地代表血浆可待因浓度。C _max、 t _max和消除t _½分别为270.7 ± 136.0 ng mL ^–1、0.438 ± 0.156 小时和2.00 ± 0.534 小时。M3G 是检测到的主要代谢物 (C _max 492.7 ± 35.5 ng mL ^–1 )，其次是 C6G (C _max 96.1 ± 33.8 ng mL ^–1 ) 和 M6G (C _max 22.3 ± 4.96 ng mL ^–1 )。吗啡和去甲可待因是丰度最低的代谢物，C _max分别为 3.17 ± 0.95 和 1.42 ± 0.79 ng mL ^–1。没有观察到明显的不良或兴奋作用。

结论和临床相关性

口服后，可待因在马体内迅速代谢为吗啡、M3G、M6G、C6G 和去甲可待因。M6G（一种假定的吗啡活性代谢物）的血浆浓度与之前报道的给马服用镇痛剂量的吗啡后的浓度相当。根据药效学变量和行为观察，可待因具有良好的耐受性。