Onishi Hiraku, Yumoto Kei, Sakata Osamu
Department of Drug Delivery Research, Hoshi University, 2-4-41, Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
Curr Drug Deliv. 2017;14(5):634-640. doi: 10.2174/1567201814666170126112108.
In the previous study, buccal absorption of ritodrine (RD) hydrochloride was reported in vivo. As a result, buccal dosing of RD solution was found to be useful for the maintenance of effective plasma concentration. However, in order to find out the dosing schedule more clearly, it is important to clarify the in vivo drug behavior.
The biodistributions of RD in oral cavity and buccal mucosal were investigated in order to understand the in vivo drug behavior after the buccal application.
The pharmacokinetic parameters for 0 - infinite time and the absorption rate were calculated based on the plasma level-time profiles in the intravenous (1 mg/kg), buccal (10 mg/kg) and intragastric (10 mg/kg) dosings using rats. The drug concentrations in buccal mucosa and the remaining drug amounts in the oral cavity were examined over time after the buccal administration. From those drug distributions and drug absorption rates, the kinetic aspects were discussed.
The absolute bioavailabilities of RD were 14.2% and 4.3% in buccal and intragastric (0.043) administrations, respectively. The oral cavity concentration was quickly eliminated within 0.5 h, and then decreased slowly. In both the administration site and distant region, the mucosal RD concentrations were observed at several dozen to approximately 100 μg/g during 0.5-4 h, indicating the rapid diffusion in the oral cavity. For both the mucosal parts, the buccal mucosal level reached a maximal level at 1 h, and then was slowly eliminated. The absorption rates were not related linearly to the buccal mucosal level, suggesting that the other mucosal parts such as sublingual mucosa and tongue ventral surface should be involved considerably in the absorption.
The changes in RD concentration in oral cavity and oral mucosa showed the drug behavior in vivo. The present study revealed that RD is not accumulated in the buccal mucosa and transfers relatively fast from the oral mucosa to systemic circulation. It was suggested that the buccal dosing of RD should be acceptable even in the repeated manner as an alternative to the intravenous or oral administration of RD.
在之前的研究中，已报道盐酸利托君（RD）可经颊部吸收。结果发现，颊部给予RD溶液有助于维持有效的血浆浓度。然而，为了更清楚地确定给药方案，明确体内药物行为很重要。
研究RD在口腔和颊黏膜中的生物分布，以了解颊部给药后的体内药物行为。
根据大鼠静脉注射（1mg/kg）、颊部给药（10mg/kg）和胃内给药（10mg/kg）后的血浆浓度-时间曲线，计算0至无穷大时间的药代动力学参数及吸收速率。颊部给药后，随时间检测颊黏膜中的药物浓度及口腔内剩余的药量。根据这些药物分布和药物吸收速率，讨论动力学方面的问题。
RD颊部给药和胃内给药（0.043）的绝对生物利用度分别为14.2%和4.3%。口腔内浓度在半小时内迅速消除，然后缓慢下降。在给药部位和远处区域，0.5至4小时内黏膜中RD浓度均在几十至约100μg/g之间，表明在口腔内快速扩散。对于两个黏膜部位，颊黏膜水平在1小时达到最高，然后缓慢消除。吸收速率与颊黏膜水平并非线性相关，提示舌下黏膜和舌腹面等其他黏膜部位在吸收中也有相当大的作用。
口腔和口腔黏膜中RD浓度的变化显示了体内药物行为。本研究表明，RD不会在颊黏膜中蓄积，而是从口腔黏膜相对快速地转运至体循环。提示即使重复给药，RD颊部给药作为静脉或口服给药的替代方式也是可以接受的。
