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目的:建立测定大鼠血浆氯胺酮浓度的反相高效液相色谱外标法,考查氯胺酮贴剂在大鼠体内的血浆药动学。方法:24只SD大鼠随机分为4组,以氯胺酮注射液10 mg·kg-1腹腔注射为对照组,以20,100,500 mg氯胺酮贴剂经皮给药为实验组。于不同时间点采血,血浆样品经处理后,采用RP-HPLC外标法测定大鼠血浆氯胺酮浓度,色谱柱为Syncronis C18柱(4.6mm×250 mm,5μm),流动相为乙腈-甲醇-0.01%三乙胺(33∶45∶22),流速为0.8 ml·min-1,柱温25℃,检测波长220 nm。采用DAS软件计算药代参数。对各组药代参数MRT0-t、t1/2z、tmax、Cmax进行方差分析(α=0.05)。结果:RP-HPLC外标法氯胺酮最低检测限0.05μg·ml-1,在0.1~20μg·ml-1范围内,线性关系良好,Y=33.321X-0.467 3,R2=0.998 9,日内、日间RSD均小于10%。氯胺酮贴剂经皮给药20 mg最低检测限下未检出;100 mg、500 mg经皮给药组的MRT0-t、t1/2z、tmax较腹腔注射组延长,差异具有统计学意义(P<0.05),Cmax无显著统计学差异(P>0.05);500 mg剂量组MRT0-t、t1/2z、tmax、Cmax稍高于100 mg剂量组,差异具有统计学意义(P<0.05)。结论:RP-HPLC外标法操作简便,准确可靠,适用于血浆氯胺酮浓度测定。氯胺酮贴剂经皮给药具有一定的缓释作用,增大贴剂含药量,可延长药物滞留时间及药物半衰期,提高血药峰浓度。该结果可为氯胺酮新剂型的研发及临床应用提供参考。
OBJECTIVE: To establish a RP-HPLC method for the determination of ketamine concentration in rat plasma and to investigate the plasma pharmacokinetics of ketamine in rats. Methods: Twenty-four Sprague-Dawley rats were randomly divided into 4 groups. The ketamine injection 10 mg · kg-1 was intraperitoneally injected into the control group, and the experimental group received 20,100,500 mg ketamine patch transdermally. Blood samples were collected at different time points. After plasma samples were processed, the concentration of ketamine in rat plasma was determined by RP-HPLC external standard method. The mobile phase consisted of Syncronis C18 column (4.6 mm × 250 mm, 5 μm) with acetonitrile-methanol-0.01 % Triethylamine (33:45:22), the flow rate was 0.8 ml · min-1, the column temperature was 25 ℃ and the detection wavelength was 220 nm. DAS software was used to calculate the pharmacokinetic parameters. The analysis of variance (α = 0.05) was made on MRT0-t, t1 / 2z, tmax and Cmax in each group. Results: The minimum detectable limit of ketamine by RP-HPLC was 0.05μg · ml-1, with good linearity in the range of 0.1 ~ 20μg · ml-1, Y = 33.321X-0.467 3, R2 = 0.998 9, Inter-RSD is less than 10%. Ketamine patch transdermal administration of 20 mg minimum detection limit was not detected; 100 mg, 500 mg transdermal delivery group MRT0-t, t1 / 2z, tmax prolonged compared with the intraperitoneal injection group, the difference was statistically significant (P (P <0.05). There was no significant difference in Cmax between the two groups (P> 0.05). The MRT0-t, t1 / 2z, tmax and Cmax in the 500 mg group were slightly higher than those in the 100 mg group (P <0.05). Conclusion: RP-HPLC external standard method is simple, accurate and reliable, suitable for the determination of plasma ketamine concentration. Transdermal administration of ketamine patch has a certain sustained release effect, increasing the amount of patch containing drug can extend the drug retention time and drug half-life and increase peak plasma concentration. The results provide a reference for the development and clinical application of ketamine new dosage form.