Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI, USA.
Biochem Pharmacol. 2019 Oct;168:57-64. doi: 10.1016/j.bcp.2019.06.013. Epub 2019 Jun 14.
Gemcitabine is a widely used chemotherapeutic drug that is administered via intravenous infusion due to a low oral bioavailability of only 10%. This low oral bioavailability is believed to be the result of gemcitabine's low intestinal permeability and oral absorption, followed by significant presystemic metabolism. In the present study, we sought to define the mechanisms of gemcitabine intestinal permeability, the potential for saturation of intestinal uptake, and the transporter(s) responsible for mediating the oral absorption of drug using in situ single-pass intestinal perfusions in mice. Concentration-dependent studies were performed for gemcitabine over 0.5-2000 μM, along with studies of 5 μM gemcitabine in a sodium-containing buffer ± thymidine (which can inhibit concentrative (i.e., CNT1 and CNT3) and equilibrative (i.e., ENT1 and ENT2) nucleoside transporters) or dilazep (which can inhibit ENT1 and ENT2), or in a sodium-free buffer (which can inhibit CNT1 and CNT3). Our findings demonstrated that gemcitabine was, in fact, a high-permeability drug in the intestine at low concentrations, that jejunal uptake of gemcitabine was saturable and mediated almost exclusively by nucleoside transporters, and that jejunal flux was mediated by both high-affinity, low-capacity (K = 27.4 µM, V = 3.6 pmol/cm/s) and low-affinity, high-capacity (K = 700 µM, V = 35.9 pmol/cm/s) transport systems. Thus, CNTs and ENTs at the apical membrane allow for gemcitabine uptake from the lumen to enterocyte, whereas ENTs at the basolateral membrane allow for gemcitabine efflux from the enterocyte to portal venous blood.
吉西他滨是一种广泛使用的化疗药物，由于其口服生物利用度仅为 10%，因此只能通过静脉输注给药。这种低口服生物利用度被认为是吉西他滨低肠道通透性和口服吸收的结果，随后是显著的首过代谢。在本研究中，我们试图确定吉西他滨肠道通透性的机制、肠道摄取的饱和潜力以及介导药物口服吸收的转运体，使用小鼠原位单次肠灌注。进行了浓度依赖性研究，吉西他滨浓度为 0.5-2000μM，同时还研究了 5μM 吉西他滨在含钠缓冲液中的吸收±胸苷（可抑制浓缩型（即 CNT1 和 CNT3）和平衡型（即 ENT1 和 ENT2）核苷转运体）或地拉卓（可抑制 ENT1 和 ENT2），或在不含钠的缓冲液中（可抑制 CNT1 和 CNT3）。我们的研究结果表明，吉西他滨实际上是一种低浓度下具有高通透性的药物，吉西他滨在空肠中的摄取是可饱和的，几乎完全由核苷转运体介导，而空肠通量是由高亲和力、低容量（K=27.4μM，V=3.6pmol/cm/s）和低亲和力、高容量（K=700μM，V=35.9pmol/cm/s）转运系统介导的。因此，顶端膜上的 CNTs 和 ENTs 允许吉西他滨从腔内向肠上皮细胞摄取，而基底外侧膜上的 ENTs 允许吉西他滨从肠上皮细胞向门静脉血液流出。
