Characterization of β‐adrenoceptor antagonists as substrates and inhibitors of the drug transporter P‐glycoprotein¹

Abstract

Transporter proteins such as P-glycoprotein are major determinants of intracellular drug concentrations. Moreover, inhibition or induction of transporters is an important mechanism underlying drug interactions in humans. However, very little is known whether beta-adrenoceptor antagonists are substrates and/or inhibitors of P-glycoprotein. Therefore, we investigated the P-glycoprotein-mediated transport of propranolol, metoprolol, bisoprolol, carvedilol and sotalol in P-glycoprotein-expressing Caco-2 monolayers and inhibition of P-glycoprotein-mediated digoxin transport by the beta-adrenoceptor antagonists. A significant inhibition of polarized, basal to apical drug transport by the P-glycoprotein inhibitor PSC-833 was observed for bisoprolol (0.5 and 5 microm) and carvedilol (0.5 microm). Moreover, propranolol and carvedilol inhibited P-glycoprotein-mediated digoxin transport with IC(50) values of 24.8 and 0.16 microm, respectively, whereas metoprolol and sotalol had no effect. Bisoprolol significantly inhibited directional digoxin transport at 50 and 250 microm by 31% and 44%, respectively. Taken together, P-glycoprotein is likely to be one determinant of bisoprolol and carvedilol disposition in humans. In addition, the beta-adrenoceptor antagonists propranolol and carvedilol significantly inhibit P-glycoprotein function thereby possibly contributing to drug interactions in humans (e.g. digoxin-carvedilol and cyclosporine-carvedilol).

Carvedilol in glioma treatment alone and with imatinib in vitro

“…Additionally, CAR is able to reverse multidrug resistance to anticancer drugs through p-Gp inhibition. The major molecular targets of CAR include the membrane adrenoreceptors (ß-1, ß-2 and ·-1), growth factor receptors including platelet-derived growth factor receptors (PDGFr), reactive oxygen species, ion channels (K + and Ca 2+ ), p-Gp and mitochondria (16)(17)(18)(19)(20)(21)(22).…”

The Use of Microdialysis for the Study of Drug Kinetics: Central Nervous System Pharmacokinetics of Diphenhydramine in Fetal, Newborn, and Adult Sheep

“…Moriki et al (2005) have provided evidence that P-glycoprotein acts as BBB efflux transporter for this compound. However, DPHM is not a P-glycoprotein substrate (Chen et al, 2003), although we have previously shown that propranolol, which inhibits P-glycoprotein (Bachmakov et al, 2006), significantly increases the brain/plasma ratios of DPHM in adult sheep (Au-Yeung et al, 2006). The identity of CNS efflux transporter for DPHM remains to be determined.…”

Successful Long-Term Treatment of Cerebral Nocardiosis with Unexpectedly Low Doses of Linezolid in an Immunocompromised Patient Receiving Complex Polytherapy

“…This suggests that the linezolid-omeprazole interaction could be particularly relevant among poor metabolizers of CYP2C19. However, it has also been found that for barnidipine and carvedilol the IC 50 s for inhibition of P-gp-mediated transport were even lower (8.6 M for barnidipine [7] and 0.16 M for carvedilol [2]) and in the range of their respective plasma concentrations. This suggests that linezolid overexposure could be particularly relevant among patients who receive cotreatment with all of these different P-gp inhibitors.…”

“…It has been recently suggested that linezolid may be a substrate of P-glycoprotein (P-gp) and that significant overexposure may occur in the presence of some P-gp inhibitors, namely, omeprazole, amiodarone, and amlodipine (13). Interestingly, three of the drugs of the complex polytherapy of our patient, namely, omeprazole, barnidipine, and carvedilol, are potent P-gp inhibitors (2,8,12). Of note, the half-maximal inhibitory concentration (IC 50 ) of omeprazole against P-gp-mediated transport was found to be 17.7 M, which is higher than its expected plasma concentrations at therapeutic doses, but not if considering poor metabolizers of CYP2C19 (12).…”