Wong Yin Cheong, Qian Shuai, Zuo Zhong
School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Room 801C, Lo Kwee-Seong Integrated Biomedical Sciences Building, Shatin, New Territories, Hong Kong.
Pharm Res. 2014 Aug;31(8):2107-23. doi: 10.1007/s11095-014-1312-8. Epub 2014 Feb 20.
To investigate the pharmacokinetic differences between the common nasal delivery models.
In three different rat models [long-term anesthetized (with nasal surgery), short-term anesthetized (without nasal surgery) and conscious models], tacrine and loxapine were administered via nasal, intravenous and oral routes, and the plasma pharmacokinetics were compared among different models.
Systemic exposures of both drugs and their metabolites were consistently higher in long-term anesthetized model after all routes of administration in comparison to that of conscious model. Nasal bioavailabilities in long-term anesthetized model (tacrine 83%, loxapine 97%) were much higher than that in conscious model (tacrine 10%, loxapine 46%). Further studies on tacrine and its metabolites demonstrated no significant difference in t1/2 between short-term anesthetized and conscious models after all routes of administration; however, long-term anesthetized model showed significantly longer t1/2. Regarding the pharmacokinetic parameters (Cmax, Tmax, AUC, bioavailability) of tacrine and its metabolites, short-term anesthetized model resembled closer to conscious model than long-term anesthetized model.
Plasma clearances of tacrine, loxapine, and their metabolites were much slower in the long-term anesthetized model of nasal delivery probably due to suppressed hepatic and renal clearances, while the short-term anesthetized model imposed less impact on tacrine pharmacokinetics and metabolism.
研究常见鼻腔给药模型之间的药代动力学差异。
在三种不同的大鼠模型[长期麻醉（行鼻腔手术）、短期麻醉（不行鼻腔手术）和清醒模型]中，通过鼻腔、静脉和口服途径给予他克林和洛沙平，并比较不同模型之间的血浆药代动力学。
与清醒模型相比，在所有给药途径后，长期麻醉模型中两种药物及其代谢物的全身暴露量始终更高。长期麻醉模型中的鼻腔生物利用度（他克林83%，洛沙平97%）远高于清醒模型（他克林10%，洛沙平46%）。对他克林及其代谢物的进一步研究表明，在所有给药途径后，短期麻醉模型和清醒模型之间的t1/2无显著差异；然而，长期麻醉模型的t1/2明显更长。关于他克林及其代谢物的药代动力学参数（Cmax、Tmax、AUC、生物利用度），短期麻醉模型比长期麻醉模型更接近清醒模型。
在长期麻醉的鼻腔给药模型中，他克林、洛沙平和它们代谢物的血浆清除率可能由于肝和肾清除率受抑制而明显减慢，而短期麻醉模型对他克林的药代动力学和代谢影响较小。
