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- Title
Characterization of β-adrenoceptor antagonists as substrates and inhibitors of the drug transporter P-glycoprotein.
- Authors
Bachmakov, Iouri; Werner, Ulrike; Endress, Beate; Auge, Daniel; Fromm, Martin F.
- 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 β-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 β-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 μm) and carvedilol (0.5 μm). Moreover, propranolol and carvedilol inhibited P-glycoprotein-mediated digoxin transport with IC50 values of 24.8 and 0.16 μm, respectively, whereas metoprolol and sotalol had no effect. Bisoprolol significantly inhibited directional digoxin transport at 50 and 250 μm 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 β-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).
- Subjects
ADRENERGIC beta agonists; P-glycoprotein; DRUG interactions; PROPRANOLOL; METOPROLOL; BISOPROLOL
- Publication
Fundamental & Clinical Pharmacology, 2006, Vol 20, Issue 3, p273
- ISSN
0767-3981
- Publication type
Article
- DOI
10.1111/j.1472-8206.2006.00408.x