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Does protein binding modulate the effect of angiotensin II receptor antagonists?
Marc P Maillard
Division of Hypertension and Vascular Medicine, Lausanne University Hospital, CH-1011 Lausanne, Switzerland, Marc.Maillard{at}chuv.hospvd.ch
Catherine Centeno
Division of Hypertension and Vascular Medicine, Lausanne University Hospital, CH-1011 Lausanne, Switzerland
Åsa Frostell-Karlsson
Biacore AB, S-754 50 Uppsala, Sweden
Hans R Brunner
Division of Hypertension and Vascular Medicine, Lausanne University Hospital, CH-1011 Lausanne, Switzerland
Michel Burnier
Division of Hypertension and Vascular Medicine, Lausanne University Hospital, CH-1011 Lausanne, Switzerland
Introduction
Angiotensin II AT 1-receptor antagonists are highly bound to plasma proteins ( 99%). With some antagonists, such as DuP-532, the protein binding was such that no efficacy of the drug could be demonstrated clinically. Whether protein binding interferes with the efficacy of other antagonists is not known. We have therefore investigated in vitro how plasma proteins may affect the antagonistic effect of different AT1-receptor antagonists.
Methods
A radio-receptor binding assay was used to analyse the interaction between proteins and the ability of various angiotensin II (Ang II) antagonists to block AT1-receptors. In addition, the Biacore technology, a new technique which enables the real-time monitoring of binding events between two molecules, was used to evaluate the dissociation rate constants of five AT1-receptor antagonists from human serum albumin.
Results
The in vitro AT 1-antagonistic effects of different Ang II receptor antagonists were differentially affected by the presence of human plasma, with rightward shifts of the IC50 ranging from one to several orders of magnitude. The importance of the shift correlates with the dissociation rate constants of these drugs from albumin. Our experiments also show that the way that AT1-receptor antagonists bind to proteins differs from one compound to another. These results suggest that the interaction with plasma proteins appears to modulate the efficacy of some Ang II antagonists.
Conclusion
Although the high binding level of Ang II receptor antagonist to plasma proteins appears to be a feature common to this class of compounds, the kinetics and characteristics of this binding is of great importance. With some antagonists, protein binding interferes markedly with their efficacy to block AT1-receptors.
Key Words: AT1-receptor antagonists • protein binding • pharmacokinetic
References
- Burnier M., Brunner HR Angiotensin II receptor antagonist. Lancet 2000;355:637-45.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Mazzolai L., Maillard M., Rossat J., Nussberger J., Brunner HR, Burnier M. Angiotensin II receptor blockade in normotensive subjects: A direct comparison of three AT1 receptor antagonists. Hypertension 1999;33:850-5.[Abstract/Free Full Text]
- Csajka C., Buclin T., Brunner HR, Biollaz J. Pharmacokineticpharmacodynamic profile of angiotensin II receptor antagonists. Clin Pharmacokinet 1997;32:1-29.[Web of Science][Medline]
[Order article via Infotrieve]
- Goldberg MR, Lo MW, Christ DD et al. DuP-532, an angiotensin II receptor antagonist: first administration and comparison with losartan. Clin Pharmacol Ther 1997;61:59-69.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Wong PC, Hart SD, Chiu AT et al. Pharmacology of DuP-532, a selective and noncompetitive AT1 receptor antagonist. J Pharmacol Exp Ther 1991;259:861-70.[Abstract/Free Full Text]
- ChiuAT, Carini DJ, Duncia JV et al. DUP-532: a second generation of nonpeptide angiotensin II receptor antagonists. Biochem Biophys Res Comm 1991;177(1):209-17.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Maillard M., Mazzolai L., Daven V. et al. Assessment of angiotensin II-receptor blockade in humans using a standardised angiotensin II-receptor binding assay. Am J Hypertens 1999;12:1201-8.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Maillard M., Rossat J., Nussberger J. et al. Pharmacological profile of UR-7247, an orally active angiotensin II receptor antagonist in healthy volunteers. J Cardiovasc Pharmacol 2000;35:383-9.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Maillard M., Rossat J., Brunner HR, Burnier M. Tasosartan, enoltasosartan, and angiotensin II receptor blockade, the confounding role of protein binding. J Pharmacol Exp Ther 2000;295:649-54.[Abstract/Free Full Text]
- Sjöholm I., Ekman B., Kober A., Ljungstedt-Pahlman I., Seiving B., Sjödin T. Binding of drugs to human serum albumin XI: the specificity of three binding sites as studied with albumin immobilized in microparticles. Mol Pharmacol 1979;16:767-77.[Abstract/Free Full Text]
- Lama JJ, Haughey DB Disopyramide binding to serum protein in man and animals. Drug Metab Disposit 1981;9:582-3.[Web of Science][Medline]
[Order article via Infotrieve]
- Israili ZH Clinical pharmacokinetics of angiotensin II (AT1) receptor blockers in hypertension. J Hum Hypertens 2000;14:S73-S86.[CrossRef][Web of Science][Medline]
[Order article via Infotrieve]
- Morsing P.,Adler G., Brandt-Eliasson U. et al. Mechanistic differences of various AT1-receptor blockers in isolated vessels of different origin. Hypertension 1999;33:1406-13.[Abstract/Free Full Text]
Journal of Renin-Angiotensin-Aldosterone System, Vol. 2, No. 1 suppl,
S54-S58 (2001)
DOI: 10.1177/14703203010020010901
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