Wandel Christoph, Kim Richard, Wood Margaret, Wood Alastair
Division of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee, USA.
Anesthesiology. 2002 Apr;96(4):913-20. doi: 10.1097/00000542-200204000-00019.
The efflux transporter P-glycoprotein, a member of the adenosine triphosphate-binding cassette superfamily, is a major determinant of the pharmacokinetics and pharmacodynamics of the opioid loperamide, a well-recognized antidiarrheal agent. Animal studies indicate that P-glycoprotein limits morphine entry into the brain. In this study, the authors examined whether other opioids of importance to anesthesiologists such as fentanyl, sufentanil, and alfentanil, and also morphine-6-glucuronide and morphine-3-glucuronide, are P-glycoprotein substrates and whether, in turn, these opioids act also as P-glycoprotein inhibitors.
The transcellular movement of the various opioids, including loperamide and morphine, was assessed in L-MDR1 (expressing P-glycoprotein) and LLC-PK1 cell monolayers (P-glycoprotein expression absent). A preferential basal-to-apical versus apical-to-basal transport in the L-MDR cells but not the LLC-PK1 cells is seen for P-glycoprotein substrates. In addition, the effect of the various opioids on the transcellular movement of the prototypical P-glycoprotein substrate digoxin was examined in Caco-2 cell monolayers. IC50 values were calculated according to the Hill equation.
Loperamide was a substrate showing high dependence on P-glycoprotein in that basal-apical transport was nearly 10-fold greater than in the apical-basal direction in L-MDRI cells. Morphine also showed a basal-to-apical gradient in the L-MDR1 cell monolayer, indicating that it too is a P-glycoprotein substrate, but with less dependence than loperamide in that only 1.5-fold greater basal-apical directional transport was observed. Fentanyl, sufentanil, and alfentanil did not behave as P-glycoprotein substrates, whereas the morphine glucuronides did not cross the cell monolayers at all, whether P-glycoprotein was present or not. Loperamide, sufentanil, fentanyl, and alfentanil inhibited P-glycoprotein-mediated digoxin transport in Caco-2 cells with IC50 values of 2.5, 4.5, 6.5, and 112 microm, respectively. Morphine and its glucuronides (20 microm) did not inhibit digoxin (5 microm) transport in Caco-2 cells, and therefore IC50 values were not determined.
Opioids have a wide spectrum of P-glycoprotein activity, acting as both substrates and inhibitors, which might contribute to their varying central nervous system-related effects.
外排转运体P-糖蛋白是三磷酸腺苷结合盒超家族的成员，是公认的止泻药阿片类洛哌丁胺药代动力学和药效学的主要决定因素。动物研究表明，P-糖蛋白限制吗啡进入大脑。在本研究中，作者研究了麻醉医生所关注的其他阿片类药物，如芬太尼、舒芬太尼和阿芬太尼，以及吗啡-6-葡萄糖醛酸苷和吗啡-3-葡萄糖醛酸苷是否为P-糖蛋白底物，以及这些阿片类药物是否也作为P-糖蛋白抑制剂。
在L-MDR1（表达P-糖蛋白）和LLC-PK1细胞单层（无P-糖蛋白表达）中评估包括洛哌丁胺和吗啡在内的各种阿片类药物的跨细胞转运。对于P-糖蛋白底物，在L-MDR细胞中观察到从基底到顶端的优先转运，而在LLC-PK1细胞中未观察到。此外，在Caco-2细胞单层中研究了各种阿片类药物对典型P-糖蛋白底物地高辛跨细胞转运的影响。根据希尔方程计算IC50值。
洛哌丁胺是一种对P-糖蛋白高度依赖的底物，在L-MDR1细胞中，从基底到顶端的转运比从顶端到基底的转运大近10倍。吗啡在L-MDR1细胞单层中也显示出从基底到顶端的梯度，表明它也是一种P-糖蛋白底物，但依赖性比洛哌丁胺小，因为观察到从基底到顶端的定向转运仅大1.5倍。芬太尼、舒芬太尼和阿芬太尼不是P-糖蛋白底物，而无论是否存在P-糖蛋白，吗啡葡萄糖醛酸苷根本不穿过细胞单层。洛哌丁胺、舒芬太尼、芬太尼和阿芬太尼在Caco-2细胞中抑制P-糖蛋白介导的地高辛转运，IC50值分别为2.5、4.5、6.5和112 μmol。吗啡及其葡萄糖醛酸苷（20 μmol）在Caco-2细胞中不抑制地高辛（5 μmol）转运，因此未测定IC50值。
阿片类药物具有广泛的P-糖蛋白活性，既作为底物又作为抑制剂，这可能导致它们产生不同的中枢神经系统相关效应。
