Kinetic model to predict the absorption of nasally applied drugs from in vitro transcellular permeability of drugs.
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.
Furubayashi
Tomoyuki
T
School of Pharmacy, Shujitsu University, Okayama, Japan. t-furu@shujitsu.ac.jp
Kamaguchi
Akiko
A
Kawaharada
Kazushi
K
Masaoka
Yoshie
Y
Kataoka
Makoto
M
Yamashita
Shinji
S
Higashi
Yutaka
Y
Sakane
Toshiyasu
T
D000042:Absorption; D000281:Administration, Intranasal; D000818:Animals; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects*; D006801:Humans; D007444:Inulin / Q000008:administration & dosage / Q000493:pharmacokinetics; D008297:Male; D008954:Models, Biological; D009297:Nasal Mucosa / Q000378:metabolism*; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D010599:Pharmacokinetics; D011237:Predictive Value of Tests; D051381:Rats; D017208:Rats, Wistar
D004364:Pharmaceutical Preparations; D007444:Inulin