Sinko P J, Hu P, Waclawski A P, Patel N R
Department of Pharmaceutics, College of Pharmacy, Rutgers University, Piscataway, NJ 08855, USA.
J Pharm Sci. 1995 Aug;84(8):959-65. doi: 10.1002/jps.2600840811.
The intestinal transport of didanosine (ddl), a nucleoside analog used in the treatment of human immunodeficiency virus (HIV) infection, was characterized using in situ and in vitro techniques. The zero-trans uptake of ddl in rat intestinal brush border membrane vesicles (BBMV) was linear over the range of 1 microM to 50 mM, ruling out a significant carrier-mediated absorption component. The lack of carrier-mediated transport was confirmed in a second species (rabbit). In order to quantitate the convective (Pconv) and diffusive (Pdiff) components of ddl intestinal permeability, the steady state wall permeability (Pw) was determined using an established perfusion technique in rats. Even though baseline Pw (pH 6.5, 290 mosm/kg, no modulator) and fluid absorption results were similar to those of furosemide, the ratios (ddl:furosemide) of Pdiff and phi, the sieving coefficient, were 0.31:1 and 1.70:1, respectively, demonstrating that ddl's Pdiff is low and Pconv is high relative to furosemide's, suggesting significant paracellular absorption of ddl. The apparent diffusive absorptive clearances (P'app) of ddl and furosemide were determined in BBMV, which lack functional tight junctions, and the ratios (ddl:furosemide) of P'app in rat and rabbit were 0.23:1 and 0.24:1, respectively. The BBMV results demonstrate that the majority of ddl intestinal transport does not occur by passive membrane diffusion, confirming the single pass intestinal perfusion (SPIP) findings. The results of these studies suggest that ddl is transported by nonfacilitated membrane and paracellular diffusion with paracellular transport being responsible for the majority of ddl absorption from the intestine.
去羟肌苷（ddl）是一种用于治疗人类免疫缺陷病毒（HIV）感染的核苷类似物，其肠道转运过程通过体内和体外技术进行了表征。ddl在大鼠肠道刷状缘膜囊泡（BBMV）中的零转运摄取在1 microM至50 mM范围内呈线性，排除了显著的载体介导吸收成分。在第二个物种（兔子）中也证实了缺乏载体介导的转运。为了定量ddl肠道通透性的对流（Pconv）和扩散（Pdiff）成分，使用既定的灌注技术在大鼠中测定了稳态壁通透性（Pw）。尽管基线Pw（pH 6.5，290 mosm/kg，无调节剂）和液体吸收结果与呋塞米相似，但Pdiff与筛分系数phi的比值（ddl:呋塞米）分别为0.31:1和1.70:1，表明相对于呋塞米，ddl的Pdiff较低而Pconv较高，提示ddl存在显著的细胞旁吸收。在缺乏功能性紧密连接的BBMV中测定了ddl和呋塞米的表观扩散吸收清除率（P'app），大鼠和兔子中P'app的比值（ddl:呋塞米）分别为0.23:1和0.24:1。BBMV结果表明，ddl的肠道转运大部分并非通过被动膜扩散发生，这证实了单通道肠道灌注（SPIP）的研究结果。这些研究结果表明，ddl通过非易化膜和细胞旁扩散进行转运，其中细胞旁转运是ddl从肠道吸收的主要方式。
