Matsui Kazuki, Tsume Yasuhiro, Amidon Gregory E, Amidon Gordon L
†College of Pharmacy, University of Michigan, 428 Church Street, Ann Arbor, Michigan 48109-1065, United States.
‡Pharmacokinetics and Safety Laboratory, Discovery Research, Pharmaceutical Research Center, Mochida Pharmaceutical Company Limited, 722 Uenohara, Jimba, Gotemba, Shizuoka 412-8524, Japan.
Mol Pharm. 2015 Jul 6;12(7):2418-28. doi: 10.1021/acs.molpharmaceut.5b00135. Epub 2015 May 27.
Weakly basic drugs typically exhibit pH-dependent solubility in the physiological pH range, displaying supersaturation or precipitation along the gastrointestinal tract. Additionally, their oral bioavailabilities may be affected by coadministration of acid-reducing agents that elevate gastric pH. The purpose of this study was to assess the feasibility of a multicompartmental in vitro dissolution apparatus, Gastrointestinal Simulator (GIS), in predicting in vivo dissolution of certain oral medications. In vitro dissolution studies of fluconazole, a BCS class I, and dipyridamole, a BCS class II weak bases (class IIb), were performed in the GIS as well as United States Pharmacopeia (USP) apparatus II and compared with the results of clinical drug-drug interaction (DDI) studies. In both USP apparatus II and GIS, fluconazole completely dissolved within 60 min regardless of pH, reflecting no DDI between fluconazole and acid-reducing agents in a clinical study. On the other hand, seven-fold and 15-fold higher concentrations of dipyridamole than saturation solubility were observed in the intestinal compartments in GIS with gastric pH 2.0. Precipitation of dipyridamole was also observed in the GIS, and the percentage of dipyridamole in solution was 45.2 ± 7.0%. In GIS with gastric pH 6.0, mimicking the coadministration of acid-reducing agents, the concentration of dipyridamole was equal to its saturation solubility, and the percentage of drug in solution was 9.3 ± 2.7%. These results are consistent with the clinical DDI study of dipyridamole with famotidine, which significantly reduced the Cmax and area under the curve. An In situ mouse infusion study combined with GIS revealed that high concentration of dipyridamole in the GIS enhanced oral drug absorption, which confirmed the supersaturation of dipyridamole. In conclusion, GIS was shown to be a useful apparatus to predict in vivo dissolution for BCS class IIb drugs.
弱碱性药物通常在生理pH范围内表现出pH依赖性溶解度，在胃肠道中会出现过饱和或沉淀现象。此外，它们的口服生物利用度可能会受到提高胃pH值的抑酸剂联合给药的影响。本研究的目的是评估一种多隔室体外溶出装置——胃肠模拟器（GIS）预测某些口服药物体内溶出的可行性。在GIS以及美国药典（USP）装置II中对BCS I类的氟康唑和BCS II类弱碱（IIb类）双嘧达莫进行了体外溶出研究，并与临床药物相互作用（DDI）研究结果进行了比较。在USP装置II和GIS中，氟康唑在60分钟内均完全溶解，与pH无关，这反映了在临床研究中氟康唑与抑酸剂之间不存在DDI。另一方面，在胃pH值为2.0的GIS的肠道隔室中，观察到双嘧达莫的浓度比饱和溶解度高7倍和15倍。在GIS中也观察到了双嘧达莫的沉淀，溶液中双嘧达莫的百分比为45.2±7.0%。在模拟抑酸剂联合给药的胃pH值为6.0的GIS中，双嘧达莫的浓度等于其饱和溶解度，溶液中药物的百分比为9.3±2.7%。这些结果与双嘧达莫与法莫替丁的临床DDI研究一致，法莫替丁显著降低了Cmax和曲线下面积。一项结合GIS的原位小鼠灌注研究表明，GIS中高浓度的双嘧达莫增强了口服药物吸收，这证实了双嘧达莫的过饱和现象。总之，GIS被证明是一种预测BCS IIb类药物体内溶出的有用装置。
