Kuo S M, Whitby B R, Artursson P, Ziemniak J A
Department of Drug Disposition, Rhône-Poulenc Rorer Central Research, Collegeville, Pennsylvania 19426.
Pharm Res. 1994 May;11(5):648-53. doi: 10.1023/a:1018959809352.
The contribution of the intestine to the nonlinear absorption of celiprolol in the rat was studied. After intravenous administration of 14C-celiprolol to bile duct-cannulated rats, approximately 9% of the dose was found to be associated with intestinal tissue and its contents. Microhistoautoradiography of frozen intestinal sections showed a time-dependent secretion of celiprolol from the blood into the lumen of the rat intestine. Propranolol, a lipophilic beta-blocker, was also found to be secreted into the intestine in vivo and transported in epithelial cells in both a temperature- and a pH-dependent manner, although to a lesser extent than celiprolol. Consistent with the observations in rats, transport of celiprolol from the basal-lateral to the apical side was found to dominate apical-to-basal transport using human Caco-2 cell monolayers. Additionally, using isolated rat small intestinal epithelial cells, celiprolol was found also to have a time- and temperature-dependent uptake, suggesting the involvement of a carrier-mediated system in its uptake. The uptake was inhibited by 2 mM celiprolol and propranolol and was also found to be pH dependent. Saturation of the carrier-mediated secretion of celiprolol in the intestine may result in enhanced absorption of celiprolol at high doses and account for its observed nonlinear absorption.
研究了肠道对大鼠中塞利洛尔非线性吸收的作用。给胆管插管大鼠静脉注射14C-塞利洛尔后，发现约9%的剂量与肠道组织及其内容物相关。冷冻肠切片的显微组织放射自显影显示，塞利洛尔从血液向大鼠肠腔的分泌呈时间依赖性。亲脂性β受体阻滞剂普萘洛尔在体内也被发现分泌到肠道中，并以温度和pH值依赖的方式在上皮细胞中转运，尽管程度比塞利洛尔小。与在大鼠中的观察结果一致，使用人Caco-2细胞单层发现，塞利洛尔从基底外侧到顶端侧的转运占主导地位，而顶端到基底的转运较少。此外，使用分离的大鼠小肠上皮细胞，发现塞利洛尔的摄取也具有时间和温度依赖性，这表明其摄取涉及载体介导的系统。2 mM的塞利洛尔和普萘洛尔可抑制摄取，并且还发现摄取依赖于pH值。肠道中载体介导的塞利洛尔分泌饱和可能导致高剂量时塞利洛尔吸收增强，并解释其观察到的非线性吸收。
