Mitragynine is the most abundant psychoactive alkaloid derived from the leaves of Mitragyna speciosa (kratom), a tropical plant indigenous to regions of Southeast Asia. Mitragynine displays a moderate affinity to opioid receptors, and kratom is often self-prescribed to treat pain and/or opioid addiction. The purpose of this study was to investigate the safety and pharmacokinetic properties of mitragynine in the dog. Single dose oral (5 mg/kg) and intravenous (0.1 mg/kg) pharmacokinetic studies of mitragynine were performed in female beagle dogs. The plasma concentrations of mitragynine were measured using ultra-performance liquid chromatography coupled with a tandem mass spectrometer, and the pharmacokinetic properties were analyzed using non-compartmental analysis. Following intravenous administration, mitragynine showed a large volume of distribution (Vd, 6.3 ± 0.6 L/kg) and high clearance (Cl, 1.8 ± 0.4 L/h/kg). Following oral mitragynine dosing, first peak plasma (Cmax, 278.0 ± 47.4 ng/mL) concentrations were observed within 0.5 h. A potent mu-opioid receptor agonist and active metabolite of mitragynine, 7-hydroxymitragynine, was also observed with a Cmax of 31.5 ± 3.3 ng/mL and a Tmax of 1.7 ± 0.6 h in orally dosed dogs while its plasma concentrations were below the lower limit of quantification (1 ng/mL) for the intravenous study. The absolute oral bioavailability of mitragynine was 69.6%. Administration of mitragynine was well tolerated, although mild sedation and anxiolytic effects were observed. These results provide the first detailed pharmacokinetic information for mitragynine in a non-rodent species (the dog) and therefore also provide significant information for allometric scaling and dose predictions when designing clinical studies.

中文翻译：

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Mitragynine 在比格犬中的药代动力学和安全性

Mitragynine 是最丰富的精神活性生物碱，来自 Mitragyna speciosa (kratom) 的叶子，这是一种原产于东南亚地区的热带植物。Mitragynine 对阿片受体具有中等亲和力，而 kratom 通常自行开药以治疗疼痛和/或阿片类药物成瘾。本研究的目的是调查米特拉吉宁在狗中的安全性和药代动力学特性。在雌性比格犬中进行了帽柱木碱的单剂量口服 (5 mg/kg) 和静脉内 (0.1 mg/kg) 药代动力学研究。使用超高效液相色谱联用串联质谱仪测量帽柱木碱的血浆浓度，并使用非房室分析分析药代动力学特性。静脉给药后，mitragynine 显示出大的分布容积（Vd，6.3 ± 0.6 L/kg）和高清除率（Cl，1.8 ± 0.4 L/h/kg）。口服帽柱木碱给药后，在 0.5 小时内观察到第一个峰值血浆 (Cmax, 278.0 ± 47.4 ng/mL) 浓度。还观察到一种有效的 mu-阿片受体激动剂和帽柱木碱的活性代谢物 7-羟基帽柱木碱，其 Cmax 为 31.5 ± 3.3 ng/mL，Tmax 为 1.7 ± 0.6 小时，但其血浆浓度低于下限静脉内研究的定量限 (1 ng/mL)。米特拉吉宁的绝对口服生物利用度为 69.6%。尽管观察到轻度镇静和抗焦虑作用，但米特拉吉宁的给药耐受性良好。