Human drug absorption kinetics and comparison to Caco-2 monolayer permeabilities
Human drug absorption kinetics and comparison to Caco-2 monolayer permeabilities
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DOI：
10.1023/a:1011992518592
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发表时间：
1998-01-01
影响因子：
3.7
通讯作者：
Ginski, MJ
中科院分区：
文献类型：
--
作者：
Polli, JE;Ginski, MJ
目的.本研究的目的是评估三种药物的药物吸收动力学，并比较其产生的一阶肠道渗透速率常数，他们的Caco-2单层permeabilities.Methods;在体外溶解，在体内吸收分析进行了四个配方的盐酸雷尼替丁，酒石酸美托洛尔，吡罗昔康产生表观和“真正的”人类临床渗透速率常数。药物透过Caco-2细胞单层的渗透系数也被测定。体外溶出-体内吸收分析揭示了各种药物制剂的溶出和肠渗透对总体药物吸收动力学的不同相对和绝对贡献，并得出了每种药物的真实和表观人体肠渗透速率常数的估计值[雷尼替丁、美托洛尔、和吡罗昔康]。观察到表观和真实渗透速率常数与Caco-2单层渗透性的等级关系。对于渗透性最差的化合物雷尼替丁，真实渗透速率常数相对于表观渗透速率常数的降低最为显著（几乎是3倍）。雷尼替丁、美托洛尔和吡罗昔康的渗透动力学存在显著差异。剂型在人体内的吸收动力学与Caco-2单层渗透性之间存在关联的可能性，可以根据Caco-2单层渗透性值直接对人体口服吸收进行动力学解释。
Purpose. This study aims to assess the drug absorption kinetics of three drugs and compare their resulting first-order intestinal permeation rate constants to their Caco-2 monolayer permeabilities.Methods; In vitro dissolution-in vivo absorption analysis was conducted on four formulations of each ranitidine HCl, metoprolol tartrate, and piroxicam to yield apparent and "true" human clinical permeation rate constants. Drug permeability coefficients through Caco-2 monolayers were also determined.Results. In vitro dissolution-in vivo absorption analysis revealed different relative and absolute contributions of dissolution and intestinal permeation to overall drug absorption kinetics for various drug formulations and yielded estimates of each drug's true and apparent human intestinal permeation rate constant [k(p) = 0.225 hr(-1), 0.609 hr(-1), and 9.00 hr(-1) for ranitidine, metoprolol, and piroxicam, respectively]. A rank order relationship was observed for both the apparent and true permeation rate constant with Caco-2 monolayer permeability. The decrease in the true permeation rate constant relative to the apparent permeation rate constant was most significant (almost three-fold) for the least permeable compound, ranitidine.Conclusions. There were marked differences in the permeation kinetics of ranitidine, metoprolol, and piroxicam. The possibility of an association between absorption kinetics from dosage forms in humans and Caco-2 monolayer permeability may allow for a direct kinetic interpretation of human oral absorption from Caco-2 monolayer permeability values.