Annaert P, Tukker J J, van Gelder J, Naesens L, de Clercq E, van Den Mooter G, Kinget R, Augustijns P
Laboratory of Pharmacotechnology & Biopharmacy, KULeuven, Leuven, Belgium.
J Pharm Sci. 2000 Aug;89(8):1054-62. doi: 10.1002/1520-6017(200008)89:8<1054::aid-jps10>3.0.co;2-5.
Caco-2 monolayers (in vitro), rat intestinal sheets mounted in modified Ussing Chambers (ex vivo), and in situ intestinal perfusion of rat ileum were used as models to determine and compare the absorption characteristics of the antiviral agent 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA, adefovir) and its bis(pivaloyloxymethyl)-ester prodrug [bis(POM)-PMEA, adefovir dipivoxil]. Although metabolism of adefovir dipivoxil was more pronounced in the ex vivo and in situ models than in the Caco-2 system, the transport of 'total adefovir' [= adefovir dipivoxil and its metabolites mono(POM)-PMEA and adefovir] was comparable in the three models. Compared with transport of the parent compound (adefovir), use of adefovir dipivoxil resulted in a significant increase in transport of total adefovir in the in vitro ( approximately 100-fold) and the in situ ( approximately 10-fold) models; in contrast, the ex vivo method failed to demonstrate a remarkable transport enhancement when using the ester prodrug. Similar to the results obtained in the Caco-2 model, the inclusion of the P-glycoprotein inhibitor verapamil resulted in transport enhancement during in situ perfusion of rat ileum with adefovir dipivoxil; however, no effect of verapamil could be observed in the ex vivo model. The results of this study confirm the utility of both the in vitro and in situ models to assess intestinal transport and metabolism of adefovir dipivoxil. The ex vivo model appeared to be less appropriate because of its inability to discriminate transport following administration of adefovir or adefovir dipivoxil and because of the absence of an effect of verapamil on transport when using adefovir dipivoxil.
采用Caco-2单层细胞(体外)、安装在改良型尤斯灌流小室中的大鼠肠组织片(离体)以及大鼠回肠的原位肠灌注作为模型,以确定和比较抗病毒药物9-[2-(膦酰甲氧基)乙基]腺嘌呤(PMEA,阿德福韦)及其双(新戊酰氧甲基)酯前体药物[双(POM)-PMEA,阿德福韦酯]的吸收特性。尽管阿德福韦酯在离体和原位模型中的代谢比在Caco-2系统中更显著,但三种模型中“总阿德福韦”(=阿德福韦酯及其代谢产物单(POM)-PMEA和阿德福韦)的转运情况相当。与母体化合物(阿德福韦)的转运相比,在体外(约100倍)和原位(约10倍)模型中,使用阿德福韦酯导致总阿德福韦的转运显著增加;相反,在离体模型中使用酯前体药物时未能显示出显著的转运增强。与在Caco-2模型中获得的结果相似,加入P-糖蛋白抑制剂维拉帕米导致在用阿德福韦酯进行大鼠回肠原位灌注时转运增强;然而,在离体模型中未观察到维拉帕米的作用。本研究结果证实了体外和原位模型在评估阿德福韦酯肠道转运和代谢方面的实用性。离体模型似乎不太合适,因为它无法区分阿德福韦或阿德福韦酯给药后的转运情况,且在使用阿德福韦酯时维拉帕米对转运没有影响。