盐酸文拉法辛鼻喷剂在大鼠体内的药动学研究及对鼻黏膜纤毛毒性的评价

Study on the pharmacokinetics of Venlafaxine hydrochloride nasal spray in rats and its nasal mucociliary toxicity

目的研究盐酸文拉法辛（Ven）鼻喷剂在大鼠体内的药动学特征,并评价其对鼻黏膜纤毛的毒性。方法以Ven灌胃给药为对照,大鼠经鼻腔给予Ven鼻喷剂后,测定血浆中Ven的浓度并比较两种给药途径的主要药动学参数;以离体蟾蜍上颚黏膜为模型,经Ven鼻喷剂处理后,记录黏膜纤毛的持续摆动时间（LTCM）。结果 Ven在大鼠体内的药动学过程符合二室模型;Ven经鼻腔及灌胃给药后,药动学参数Tmax分别为2.67±0.82、11.67±2.58 min,Cmax分别为15.90±6.54、6.43±2.93μg·m L-1,二者比较均有统计学意义;Ven鼻喷剂的相对生物利用度（Fr）高达649.6%;经Ven鼻喷剂处理后,首次测得蟾蜍上颚黏膜的LTCM为42.2±2.6 min,纤毛摆动恢复后,再次测得LTCM为174.8±4.1 min,鼻喷剂组总的LTCM为阴性对照组的61.2%。结论 Ven鼻喷剂在大鼠体内吸收迅速,生物利用度高,且对鼻黏膜纤毛的毒性较小,是一种具有潜在开发前景的鼻用新制剂。

OBJECTIVE To study the pharmacokinetics of Venlafaxine hydrochloride（ Ven） nasal spray in rats and to investigate its nasal mucociliary toxicity. METHODS Ven plasma concentration of rats,after administration of the nasal spray,were determined using the drug solution（ ig） as reference and the main pharmacokinetic parameters of the drug were also estimated. The lasting time of ciliary movement（ LTCM） of the isolated upper palate mucosa of the toad treated with Ven nasal spray were recorded. RESULTS The pharmacokinetics profiles of Ven administered nasally or orally to the rats conformed to an open two-compartment model. The pharmacokinetic parameters of the nasal spray and oral solution were as follow：Tmaxwere 2. 67 ± 0. 82 min and 11. 67 ± 2. 58 min,Cmaxwere15. 90 ± 6. 54 μg·m L-1 and 6. 43 ± 2. 93 μg·m L-1,respectively. There was significant difference in Tmaxand Cmaxbetween nasal and oral administration routes. The Frof Ven nasal spray was up to 649. 6%. The first-time and the second time recorded LTCM of Ven nasal spray was 42. 2 ± 2. 6 min and 174. 8 ± 4. 1 min,respectively. The total LTCM for the nasal spray group was about 61. 2% of the negative control group. CONCLUSION Ven nasal spray will be a promising new dosage form with advantages such as rapid absorption,high bioavailability and lower nasal mucociliary toxicity.