Nasal drug delivery has attracted significant attention as an alternative route to deliver drugs having poor bioavailability. Large-molecule drugs, such as peptides and central nervous system drugs, would benefit from intranasal delivery. Drug absorption after intranasal application depends on the nasal retention of the drug, which is determined by the nasal mucociliary clearance. Mucociliary clearance (MC) is an important determinant of the rate and extent of nasal drug absorption. The aim of the present study was to clarify the effect of the changes in MC on in vivo drug absorption after nasal application, and to justify the pharmacokinetic model to which the MC parameter was introduced, to enable prediction of bioavailability after intranasal administration. The pharmacokinetics of norfloxacin (NFX) after intranasal administration were evaluated following the modification of nasal MC by pretreatment with the MC inhibitors propranolol and atropine and the MC enhancers terbutaline and acetylcholine chloride. From the relationship between nasal MC and bioavailability after nasal application, prediction of drug absorption was attempted on the basis of our pharmacokinetic model. Propranolol and atropine enhanced the bioavailability of NFX by 90 and 40%, respectively, while the bioavailability decreased by 30% following terbutaline and 40% following acetylcholine chloride. As a result of changes in the MC function, nasal drug absorption was changed depending on the nasal residence time of the drug. On the basis of our pharmacokinetic model, the nasal drug absorption can be precisely predicted, even when the MC is changed. This prediction system allows the quantitative evaluation of changes in drug absorption due to changes in nasal MC and is expected to contribute greatly to the development of nasal formulations.

中文翻译：

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鼻粘膜功能对大鼠鼻内给药后诺氟沙星体内吸收的影响的定量估计

鼻药物递送作为递送生物利用度差的药物的替代途径引起了广泛的关注。大分子药物，例如肽和中枢神经系统药物，将受益于鼻内给药。鼻内应用后的药物吸收取决于药物的鼻腔保留，这取决于鼻腔粘膜纤毛清除率。粘膜纤毛清除率（MC）是决定鼻腔药物吸收速率和程度的重要决定因素。本研究的目的是阐明鼻腔给药后MC变化对体内药物吸收的影响，并证明引入MC参数的药代动力学模型是合理的，从而可以预测鼻内给药后的生物利用度。鼻腔给药后，通过用MC抑制剂普萘洛尔和阿托品以及MC增强剂特布他林和乙酰胆碱氯化物预处理对鼻腔MC进行修饰后，评估了诺氟沙星（NFX）鼻内给药后的药代动力学。从鼻腔给药后鼻腔MC与生物利用度之间的关系，我们在药代动力学模型的基础上尝试预测药物的吸收。普萘洛尔和阿托品分别使NFX的生物利用度提高90％和40％，而特布他林后的生物利用度降低30％，乙酰氯胆碱的生物利用度降低40％。由于MC功能的改变，鼻药物吸收根据药物的鼻停留时间而改变。在我们的药代动力学模型的基础上，可以精确预测鼻腔吸收的药物，即使更改了MC。该预测系统可以定量评估由于鼻腔MC改变而引起的药物吸收变化，并且有望为鼻腔制剂的开发做出巨大贡献。