S(+)-盐酸氯胺酮在大鼠体内药动学研究

 目的S(+)-盐酸氯胺酮是盐酸氯胺酮右旋光学异构体,研究大鼠静脉注射给药后体内血浆药动学、组织分布、代谢及排泄特征,为临床应用提供参考依据。方法本实验采用LC-MS测定生物样品中S(+)-盐酸氯胺酮浓度。结果大鼠静脉注射不同剂量S(+)-盐酸氯胺酮(6.25,12.5,25mg·kg^-1)后,ρ_max及AUC与给药剂量呈正相关;体内分布以肾、肾上腺最高,脑、小肠、肌肉、胃、心脏等次之,肝、肺等组织水平最低。S(+)-盐酸氯胺酮静脉注射后经粪、尿、胆汁排泄,排泄量分别占给药量的0.007%,0.66%,和16%。S(+)-盐酸氯胺酮在大鼠体内可经CYP2E1,CYP3A和CYP2C同工酶代谢,氧化成去甲基代谢物和双键去甲基代谢物。结论研究S(+)-盐酸氯胺酮的血浆药动学、组织分布、代谢及排泄特征可为该药临床应用的安全性和有效性提供重要的参考依据。

Pharmacokinetics of S(+)-Ketamine in Rats

OBJECTIVE To characterize the pharmacokinetics,tissue distribution,metabolism and excretion of S(+)-ketamine in rats after intravenous administration. METHODS The concentrations of S(+)-ketamine in plasma,tissue and excrements were measured by a validated high-performance liquid chromatography-mass spectrum (LC-MS) analysis. RESULTS The ρ_max (2 760.5,4 082.2,9 653.7 μg·L^-1) and AUC_0-∞ (31 189.6,67 352.7,100 844.9 μg·min·L^-1) of S(+)-ketamine increased proportionally from 6.25 to 25 mg·kg^-1 in rats,respectively. S(+)-ketamine was readily distributed to tissue after intravenously administration of 6.25 mg·kg^-1. The highest levels of S(+)-ketamine were found in kidney and adrenal gland,followed by brain,intestine,stomach,muscle and heart. Bile elimination was the major excretion route of S(+)-ketamine in rats. The amount of S(+)-ketamine excreted from bile were about 16% of given dose,while the excretion from urine and feces was only 0.66% and 0.007% of given dose. Biotransformation of S(+)-ketamine was considered as the major clearance route in rats. The identification of metabolizing enzymes responsible for S(+)-ketamine metabolism were CYP2E1,CYP3A and CYP2C in rat liver microsomes. S(+)-ketamine was N-demethylated into norketamine,and then to its dehydrogenated norketamine in rats. CONCLUSION This present investigation on S(+)-ketamine pharmacokinetics,tissue distribution,metabolism and excretion provide important information to clinical practice,which is essential for understanding the safety and efficacy of this drug.