Evaluation of the contribution of the nasal cavity and gastrointestinal tract to drug absorption following nasal application to rats.
Drugs applied to the nose in in vivo physiologic condition undergo absorption from the nasal cavity and the gastrointestinal (GI) tract because drug solution in the nasal cavity, together with mucus layer, is cleared to pharynx and then to the GI tract by coordinated beat of the cilia on nasal epithelial cells. The purpose of this study was to develop evaluate the contribution of the nasal cavity and the GI tract to drug absorption following nasal application and to clarify the relation to the transepithelial permeability of the drug (the permeability to Caco-2 monolayer, P(Caco-2)). Male Wistar rats received intravenous, nasal, and oral drug administration and drug concentration-time profiles in plasma were determined. Fractional absorption after nasal application (Fn) and oral administration (Fpo) were calculated from the area under the curve following intravenous injection (AUCiv), nasal application (AUCn), and oral administration (AUCpo) as AUCn/AUCiv and AUCpo/AUCiv, respectively. Fractional absorption from the nasal cavity (F(NC)) and the GI tract (F(GI)) following nasal application was calculated as (Fn-Fpo)/(1-Fpo) and Fpo(1-F(NC)), respectively. The shape of the curve between F(NC) and P(Caco-2) was similar with the one observed in the case of oral bioavailability except the curve shifted right. It is noteworthy that the relation between F(GI) and P(Caco-2) showed a bell-shaped curve with peak at 10(-6) cm/s of P(Caco-2). Highly permeable drug is primarily absorbed through the nasal mucosa before it is cleared to the GI tract. With the decrease in P(Caco-2), the larger amount of the drug is cleared to the GI tract and absorption from the GI tract is increased. Poorly permeable drug, on the other hand, was absorbed neither from the nasal was nor the GI tract. These findings suggest that the primary absorption site of drug after nasal application is decided by mucociliary clearance and absorption through the nasal mucosa.
Furubayashi
Tomoyuki
T
School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Okayama 703-8516, 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
D000212:Acyclovir / Q000008:administration & dosage / Q000493:pharmacokinetics; D000281:Administration, Intranasal; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D019540:Area Under Curve; D001682:Biological Availability; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods; D041981:Gastrointestinal Tract / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics; D007408:Intestinal Absorption; D007700:Kinetics; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics; D009296:Nasal Cavity / Q000378:metabolism*; D009297:Nasal Mucosa / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D000998:Antiviral Agents; D007166:Immunosuppressive Agents; D000212:Acyclovir; D008727:Methotrexate