Kim Moon Kyoung, Han Liwei, Choi Min Koo, Han Yong-Hae, Kim Dae-Duk, Chung Suk-Jae, Shim Chang-Koo
Department of Pharmaceutics, College of Pharmacy, Seoul National University, Shilim-9-dong, Kwanak-Gu, Seoul 151-742, Korea.
J Pharm Sci. 2005 Dec;94(12):2644-55. doi: 10.1002/jps.20456.
The oral bioavailability of tributylmethyl ammonium (TBuMA), an organic cation (OC), exhibited a dose-dependency (i.e., 17, 27, and 35% at doses of 0.4, 4, or 12 micromol/kg, respectively) in the rat. Relevant mechanisms were investigated in the present study by estimating the mucosal to serosal (m-s) and serosal to mucosal (s-m) transport of TBuMA across the rat ileum in an Ussing chamber experiment. The m-s permeability rapidly increased with TBuMA concentration in the mucosal side, and then becoming constant at high TBuMA concentrations. Various studies, including temperature- and potential-dependency and inhibition experiments, revealed that carrier-mediated transport mechanisms (most likely OCT1, OCT3, and P-gp) are involved in the s-m transport of TBuMA, and the saturation of the transport at higher concentrations is responsible for the concentration-dependency in the m-s permeability or dose-dependency of the bioavailability of TBuMA. A nonlinear regression of the m-s transport, based on the assumption of a mixed process of linear diffusion and saturable efflux, exhibited a clearance (CLlinear) of 0.343 microL/min/cm2 for the passive diffusion, and an apparent Km of 241 microM for the saturable process. The Km value is consistent with the concentration range in the intestine which is expected to be achieved after the oral dosing of TBuMA at a dose of 0.4 micromol/kg (i.e., 68 approximately 185 microM). Interestingly, the m-s transport of TBuMA was increased by the presence of P-gp substrates or inhibitors in the mucosal side, but not by the mucosal presence of OCT substrates or inhibitors, suggesting that only efflux transport systems on the apical membrane (e.g., P-gp), but not those on the serosal membrane (e.g., OCT1 and OCT3), of the intestinal epithelial cells, are involved in the dose-dependency or concentration dependency. A similar relationship seems likely for drugs that are substrates of efflux transporters on the apical membrane of the intestinal epithelium.
有机阳离子三丁基甲基铵（TBuMA）在大鼠体内的口服生物利用度呈现剂量依赖性（即分别在剂量为0.4、4或12微摩尔/千克时为17%、27%和35%）。在本研究中，通过在Ussing chamber实验中估计TBuMA跨大鼠回肠的黏膜到浆膜（m-s）以及浆膜到黏膜（s-m）的转运，对相关机制进行了研究。m-s通透性随黏膜侧TBuMA浓度迅速增加，然后在高TBuMA浓度时趋于恒定。包括温度和电位依赖性以及抑制实验在内的各种研究表明，载体介导的转运机制（很可能是OCT1、OCT3和P-糖蛋白）参与了TBuMA的s-m转运，且较高浓度下转运的饱和导致了m-s通透性的浓度依赖性或TBuMA生物利用度的剂量依赖性。基于线性扩散和饱和外排混合过程的假设，对m-s转运进行非线性回归，得出被动扩散的清除率（CLlinear）为0.343微升/分钟/平方厘米，饱和过程的表观Km为241微摩尔。该Km值与在0.4微摩尔/千克剂量口服TBuMA后预期在肠道中达到的浓度范围一致（即68至185微摩尔）。有趣的是，黏膜侧存在P-糖蛋白底物或抑制剂时，TBuMA的m-s转运增加，但黏膜侧存在OCT底物或抑制剂时则不然，这表明只有肠上皮细胞顶端膜上的外排转运系统（如P-糖蛋白），而非浆膜上的（如OCT1和OCT3），参与了剂量依赖性或浓度依赖性。对于肠道上皮顶端膜上外排转运体底物的药物，可能也存在类似关系。
