Simulations of the Nonlinear Dose Dependence for Substrates of Influx and Efflux Transporters in the Human Intestine
Simulations of the Nonlinear Dose Dependence for Substrates of Influx and Efflux Transporters in the Human Intestine
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DOI：
10.1208/s12248-009-9111-6
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发表时间：
2009-06-01
期刊：
影响因子：
4.5
通讯作者：
Woltosz, Walter S.
中科院分区：
文献类型：
--
作者：
Bolger, Michael B.;Lukacova, Viera;Woltosz, Walter S.
本研究的目的是开发模拟和建模方法，用于评估肠道流入和流出转运体参与胃肠道吸收时的药代动力学。采用先进的隔室吸收转运模型(ACAT)模拟万乃洛韦、加巴喷丁和他林洛尔的吸收和药代动力学。这些药物中的每一种都是内流或外流转运体的底物，在正常治疗范围内都表现出非线性的剂量依赖关系。这些模拟包括实验获得的寡肽转运体PepT1和HPT1(Valacylovir)；系统L-氨基酸转运体LAT2和有机阳离子转运体OCTN1(加巴喷丁)；以及有机阴离子转运体(OATP1A2)和P-糖蛋白(他林洛尔)的转运体表达水平的胃肠道分布。通过假设寡肽转运体的均匀分布和万乃洛韦体外Km值的应用，模拟准确地再现了实验中的非线性剂量依赖关系。对于加巴喷丁，LAT2分布产生的模拟结果比OCTN1分布要准确得多。对于他林洛尔，OATP1A2的内流转运体分布和外流转运体P-糖蛋白在远端小肠中随着表达的增加而分布的结果最好。ACAT模型中使用的小肠和大肠的生理特性能够准确地解释本研究中所包括的三种药物在浓度和载体介导的转运中的位置和时间变化。ACAT模型再现了每种药物的非线性剂量依赖关系。
The purpose of this study was to develop simulation and modeling methods for the evaluation of pharmacokinetics when intestinal influx and efflux transporters are involved in gastrointestinal absorption. The advanced compartmental absorption and transit (ACAT) model as part of the computer program GastroPlus T was used to simulate the absorption and pharmacokinetics of valacyclovir, gabapentin, and talinolol. Each of these drugs is a substrate for an influx or efflux transporter and all show nonlinear dose dependence within the normal therapeutic range. These simulations incorporated the experimentally derived gastrointestinal distributions of transporter expression levels for oligopeptide transporters PepT1 and HPT1 (valacyclovir); System L-amino acid transporter LAT2 and organic cation transporter OCTN1 (gabapentin); and organic anion transporter (OATP1A2) and P-glycoprotein (talinolol). By assuming a uniform distribution of oligopeptide transporter and by application of the in vitro Km value for valacyclovir, the simulations accurately reproduced the experimental nonlinear dose dependence. For gabapentin, LAT2 distribution produced simulation results that were much more accurate than OCTN1 distributions. For talinolol, an influx transporter distribution for OATP1A2 and the efflux transporter P-glycoprotein distributed with increasing expression in the distal small intestine produced the best results. The physiological characteristics of the small and large intestines used in the ACAT model were able to accurately account for the positional and temporal changes in concentration and carrier-mediated transport of the three drugs included in this study. The ACAT model reproduced the nonlinear dose dependence for each of these drugs.