Kan W M, Liu Y T, Hsiao C L, Shieh C Y, Kuo J H, Huang J D, Su S F
Department of Pharmacology, National Cheng Kung University, Medical College, Tainan 70101, Taiwan, ROC.
Anticancer Drugs. 2001 Mar;12(3):267-73. doi: 10.1097/00001813-200103000-00012.
Etoposide, an anti-neoplastic agent and a substrate of P-glycoprotein (P-gp), exhibits variable oral bioavailability. P-gp, the multidrug resistance gene (mdr1) product, has been considered as an absorption barrier against intestinal drug absorption. Terfenadine, an antihistamine, has been shown to be a P-gp inhibitor. The current study was designed to assess the effect of hydroxyzine, an antihistamine, on the transport of etoposide in the small intestine. Everted rat gut sacs were used to determine the absorption and exsorption of etoposide under different conditions, as rhodamine 123 was chosen to evaluate the role of P-gp in the drug interaction. The results showed that the transport of etoposide was significantly increased from the luminal site to the serosal site in the jejunum by 2- and 4-fold after 90 min in the presence of hydroxyzine and quinidine, respectively. A similar trend was observed in the ileal sacs. This in vitro exsorption study also demonstrated that hydroxyzine could reduce the efflux of etoposide to the luminal site in either jejunum or ileum. The effect of hydroxyzine on the pharmacokinetics of etoposide differed by the in vivo route of administration, thus assuming clinical importance for chemotherapeutic treatment.
依托泊苷是一种抗肿瘤药物，也是P-糖蛋白（P-gp）的底物，其口服生物利用度存在差异。P-gp是多药耐药基因（mdr1）的产物，被认为是肠道药物吸收的屏障。特非那定是一种抗组胺药，已被证明是一种P-gp抑制剂。本研究旨在评估抗组胺药羟嗪对依托泊苷在小肠转运的影响。采用外翻大鼠肠囊法，在不同条件下测定依托泊苷的吸收和外排情况，选用罗丹明123评估P-gp在药物相互作用中的作用。结果表明，在存在羟嗪和奎尼丁的情况下，90分钟后，空肠中依托泊苷从肠腔侧到浆膜侧的转运分别显著增加了2倍和4倍。在回肠囊中也观察到类似趋势。这项体外外排研究还表明，羟嗪可以减少依托泊苷在空肠或回肠向肠腔侧的外排。羟嗪对依托泊苷药代动力学的影响因体内给药途径而异，因此在化疗治疗中具有临床重要性。
