Molecular Pharmaceutics Lab., College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Noji-higashi, Kusatsu, Shiga 525-8577, Japan; Department of Pharmaceutics, School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-ku, Okayama 703-8516, Japan.
Department of Pharmaceutics, School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-ku, Okayama 703-8516, Japan; Laboratory of Pharmaceutical Technology, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada, Kobe 658-8558, Japan.
Eur J Pharm Biopharm. 2020 Apr;149:145-153. doi: 10.1016/j.ejpb.2020.02.004. Epub 2020 Feb 11.
For establishing a precise system for predicting in vivo bioavailability following intranasal (IN) administration, the relationships among membrane permeability of drugs across Calu-3 cells, in situ nasal mucosal drug permeation rate, and in vivo drug absorption following IN administration were quantified. The membrane permeability coefficient (P) was determined for sixteen model drugs by in vitro permeation studies in Calu-3 cells. The drug permeation rate constant through the nasal mucosa (k) was calculated from the in situ nasal perfusion of the drug solutions in rats. Bioavailability following IN administration of six model drugs with different membrane permeabilities were determined by in vivo drug absorption studies in rats. The correlations among in vitro membrane permeability properties, in situ nasal mucosal drug permeation rate, and in vivo drug absorption following IN administration, were assessed. The significant correlation between the in vitro Calu-3 cell permeability and nasal mucosal drug permeation rate (r = 0.812, p < 0.001) indicated that nasal mucosal drug permeability is estimable from in vitro membrane permeability. Furthermore, bioavailability following IN administration significantly correlated with the in vitro P across Calu-3 cells (r = 0.984, p < 0.001), suggesting that in vivo drug absorption following IN administration can be predicted from in vitro Calu-3 membrane permeability.
为了建立一个精确的预测鼻内（IN）给药后体内生物利用度的系统，定量研究了药物穿过 Calu-3 细胞的膜通透性、原位鼻黏膜药物渗透速率和 IN 给药后体内药物吸收之间的关系。通过 Calu-3 细胞的体外渗透研究，确定了 16 种模型药物的膜渗透系数（P）。通过在大鼠中进行药物溶液的原位鼻内灌注，计算了药物通过鼻黏膜的渗透速率常数（k）。通过在大鼠中的体内药物吸收研究，确定了具有不同膜通透性的 6 种模型药物 IN 给药后的生物利用度。评估了体外膜通透性特性、原位鼻黏膜药物渗透速率和 IN 给药后体内药物吸收之间的相关性。体外 Calu-3 细胞通透性与鼻黏膜药物渗透速率之间存在显著相关性（r=0.812，p<0.001），表明可以从体外膜通透性估计鼻黏膜药物通透性。此外，IN 给药后的生物利用度与 Calu-3 细胞的体外 P 显著相关（r=0.984，p<0.001），表明可以从体外 Calu-3 细胞膜通透性预测 IN 给药后的体内药物吸收。
