Boily Marc-Olivier, Chauret Nathalie, Laterreur Julie, Leblond François A, Boudreau Chantal, Duquet Marie-Claude, Lévesque Jean-François, Ste-Marie Line, Pichette Vincent
Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont, Faculté de Médicine, Université de Montréal, Québec, Canada (M.-O.B., F.A.L., V.P.) and Vertex Pharmaceuticals Canada Incorporated, Laval, Quebec, Canada (M.-O.B., N.C., J.L., C.B., M.-C.D., J.-F.L., L.S.-M.)
Service de Néphrologie et Centre de Recherche, Hôpital Maisonneuve-Rosemont, Faculté de Médicine, Université de Montréal, Québec, Canada (M.-O.B., F.A.L., V.P.) and Vertex Pharmaceuticals Canada Incorporated, Laval, Quebec, Canada (M.-O.B., N.C., J.L., C.B., M.-C.D., J.-F.L., L.S.-M.).
Drug Metab Dispos. 2015 Dec;43(12):1960-5. doi: 10.1124/dmd.115.066357. Epub 2015 Oct 5.
1-Aminobenzotriazole (ABT) is regularly used in vivo as a nonspecific and irreversible cytochrome P450 inhibitor to elucidate the role of metabolism on the pharmacokinetic profile of xenobiotics. However, few reports have considered the recent findings that ABT can alter drug absorption or have investigated the possible differential inhibition of ABT on intestinal and hepatic metabolism. To address these uncertainties, pharmacokinetic studies under well controlled and defined ABT pretreatment conditions (50 mg/kg, 1 hour ABT i.v. and 16 hours ABT p.o.) were conducted prior to the oral administration of metoprolol, a permeable P450 probe that undergoes extensive intestinal and hepatic metabolism. The pharmacokinetic profile of metoprolol was affected differently by the two ABT pretreatments. An increase in area under the curve of 16-fold with ABT p.o. and 6.5-fold with ABT i.v. was observed compared with control. Based on in vitro studies, this difference could not be attributed to a differential inhibition of intestinal and hepatic metabolism. In the ABT i.v. pretreatment group, the increase in area under the curve was also associated with a prolonged time at maximal concentration (24-fold versus control), suggesting a delay in absorption. This was further confirmed by the administration of a charcoal meal, which resulted in a 7-fold increase in stomach weights in the 1-hour ABT pretreated groups compared with the untreated or 16-hour ABT pretreated rats. Based on these results, we recommend pretreating rats with ABT p.o. 16 hours before the administration of a test compound to preserve the inhibitory effect on intestinal and hepatic metabolism and avoid the confounding effect on drug absorption.
1-氨基苯并三唑（ABT）常用于体内作为一种非特异性、不可逆的细胞色素P450抑制剂，以阐明代谢对外源化合物药代动力学特征的作用。然而，很少有报告考虑到ABT可改变药物吸收这一最新发现，也很少有研究调查ABT对肠道和肝脏代谢可能存在的差异抑制作用。为解决这些不确定性问题，在口服美托洛尔（一种可渗透的P450探针，在肠道和肝脏中经历广泛代谢）之前，在严格控制和明确的ABT预处理条件下（50mg/kg，静脉注射ABT 1小时和口服ABT 16小时）进行了药代动力学研究。两种ABT预处理对美托洛尔的药代动力学特征产生了不同影响。与对照组相比，口服ABT时曲线下面积增加了16倍，静脉注射ABT时增加了6.5倍。基于体外研究，这种差异不能归因于对肠道和肝脏代谢的差异抑制。在静脉注射ABT预处理组中，曲线下面积的增加还与最大浓度时的时间延长有关（与对照组相比为24倍），表明吸收延迟。给予活性炭餐进一步证实了这一点，与未处理或口服ABT 16小时预处理的大鼠相比，在口服ABT 1小时预处理组中胃重量增加了7倍。基于这些结果，我们建议在给予受试化合物前16小时口服ABT预处理大鼠，以保留对肠道和肝脏代谢的抑制作用，并避免对药物吸收产生混淆效应。
