Furubayashi Tomoyuki, Kamaguchi Akiko, Kawaharada Kazushi, Masaoka Yoshie, Kataoka Makoto, Yamashita Shinji, Higashi Yutaka, Sakane Toshiyasu
School of Pharmacy, Shujitsu University, Okayama, Japan.
Biol Pharm Bull. 2007 May;30(5):1007-10. doi: 10.1248/bpb.30.1007.
The purpose of this study is to propose a kinetic model to predict the absorption of nasally applied drugs from their permeability to the Caco-2 monolayer (P(Caco-2)). Since a drug applied to the nose in an in vivo physiologic condition is translocated to the gastrointestinal (GI) tract by coordinated beats of cilia (mucociliary clearance, MC), the drug undergoes absorption both from the nasal cavity and from the GI tract. The detailed MC of the rat was examined, using inulin as a marker of the applied solution. Inulin disappeared monoexponentially from the nasal cavity, indicating that the MC can be assumed to follow first-order kinetics. From the disappearance of inulin, the first order rate constant for MC (k(MC)) was calculated as 0.0145 min(-1). In the proposed kinetic model, the fractional absorption of the drug following nasal application is predicted as the sum of F(NC) (fractional absorption from the nasal cavity) and F(GI) (fractional absorption from the GI tract), both of which are estimated indirectly from P(Caco-2). F(NC) is calculated according to the equation, k(a)/(k(a)+k(MC)), where k(a) is the absorption rate constant. Nasal drug absorption is assumed to follow first order kinetics. The k(a) of four drugs was initially calculated from k(MC) and their F(NC); thereafter, the linear relationship between k(a) and P(Caco-2), from which k(a) is predicted, was determined. F(GI) is calculated as F(p.o.)(1-F(NC)), where F(p.o.) is fractional absorption after oral administration. F(p.o.) was predicted from the previously determined sigmoid curve between F(p.o.) and P(Caco-2). The proposed kinetic model is the first estimation system for nasal drug absorption based on drug disposition after nasal application and is useful for the development of nasal dosage forms.
本研究的目的是提出一个动力学模型，以根据鼻腔给药药物对Caco-2单层细胞的渗透率（P（Caco-2））来预测其吸收情况。由于在体内生理条件下经鼻给药的药物会通过纤毛的协同摆动（黏液纤毛清除，MC）转运至胃肠道（GI），因此药物会在鼻腔和胃肠道均发生吸收。使用菊粉作为给药溶液的标志物，对大鼠的详细MC进行了研究。菊粉从鼻腔呈单指数消失，表明MC可假定遵循一级动力学。根据菊粉的消失情况，计算出MC的一级速率常数（k（MC））为0.0145 min⁻¹。在所提出的动力学模型中，鼻腔给药后药物的吸收分数预测为F（NC）（鼻腔吸收分数）和F（GI）（胃肠道吸收分数）之和，二者均根据P（Caco-2）间接估算。F（NC）根据公式k（a）/（k（a）+k（MC））计算，其中k（a）为吸收速率常数。假定鼻腔药物吸收遵循一级动力学。最初根据k（MC）及其F（NC）计算了四种药物的k（a）；此后，确定了k（a）与P（Caco-2）之间的线性关系，据此可预测k（a）。F（GI）计算为F（口服）（1 - F（NC）），其中F（口服）为口服给药后的吸收分数。F（口服）根据先前确定的F（口服）与P（Caco-2）之间的S形曲线进行预测。所提出的动力学模型是首个基于鼻腔给药后药物处置情况的鼻腔药物吸收估算系统，对鼻腔剂型的开发具有重要意义。
