Spahn-Langguth H, Langguth P
Department of Pharmaceutical Chemistry, Martin-Luther-University Halle-Wittenberg, Wolfgang-Langenbeck-Strasse 4, D-06120 Halle/Saale, Germany.
Eur J Pharm Sci. 2001 Feb;12(4):361-7. doi: 10.1016/s0928-0987(00)00191-3.
Grapefruit juice (GFJ) is known to affect the pharmacokinetics of various drugs, presumably mainly via inhibition of oxidative metabolism. In order to evaluate the effect of GFJ on P-glycoprotein-related transport processes, measurements of transport characteristics through Caco-2 monolayers and in vivo drug absorption studies were performed with the transported, yet not metabolized model compound talinolol. Apical-to-basolateral talinolol transport in the Caco-2 model at 1 mM racemate concentration was increased almost 3-fold when GFJ was present (S-talinolol P(eff): 0.16 x 10(-6) vs. 0.61 x 10(-6) cm/s without vs. with GFJ; R-talinolol P(eff): 0.19 x 10(-6) vs. 0.71 x 10(-6) cm/s without vs. with GFJ). In vivo in rats, doubled maximum plasma concentrations, enhanced AUC values (C(max) of S-talinolol: control, 77.5 ng/ml vs. GFJ, 163.6 ng/ml; C(max) of R-talinolol: control, 79.5 ng/ml vs. GFJ, 163.0 ng/ml; AUC of S-talinolol: control, 19.3 microg ml(-1)min vs. GFJ, 29.9 microg ml(-1)min; AUC of R-talinolol: control, 22.2 microg ml(-1)min vs. GFJ, 30.1 microg ml(-1)min), and decreased apparent oral clearances were found for both talinolol enantiomers when GFJ was administered together with a racemic 10 mg/kg b.w. p.o. dose. Furthermore, GFJ tended to accelerate the rate of talinolol input, but did not significantly affect terminal talinolol half-lives. It is concluded that inhibition of intestinal secretion may contribute to bioavailability enhancement upon GFJ intake.
众所周知，葡萄柚汁（GFJ）会影响多种药物的药代动力学，推测主要是通过抑制氧化代谢。为了评估GFJ对P-糖蛋白相关转运过程的影响，使用可转运但不代谢的模型化合物他林洛尔进行了通过Caco-2单层的转运特性测量和体内药物吸收研究。当存在GFJ时，在1 mM外消旋体浓度下，Caco-2模型中从顶端到基底侧的他林洛尔转运增加了近3倍（S-他林洛尔P（eff）：无GFJ时为0.16×10（-6）cm/s，有GFJ时为0.61×10（-6）cm/s；R-他林洛尔P（eff）：无GFJ时为0.19×10（-6）cm/s，有GFJ时为0.71×10（-6）cm/s）。在大鼠体内，当GFJ与10 mg/kg体重的外消旋体口服剂量一起给药时，两种他林洛尔对映体的最大血浆浓度加倍，AUC值增加（S-他林洛尔的C（max）：对照组为77.5 ng/ml，GFJ组为163.6 ng/ml；R-他林洛尔的C（max）：对照组为79.5 ng/ml，GFJ组为163.0 ng/ml；S-他林洛尔的AUC：对照组为19.3μg ml（-1）min，GFJ组为29.9μg ml（-1）min；R-他林洛尔的AUC：对照组为22.2μg ml（-1）min，GFJ组为30.1μg ml（-1）min），且表观口服清除率降低。此外，GFJ倾向于加快他林洛尔的输入速率，但对他林洛尔的终末半衰期没有显著影响。得出的结论是，抑制肠道分泌可能有助于GFJ摄入后生物利用度的提高。
