Document Detail


Enhanced photosafety of cinacalcet upon complexation with serum albumin.
MedLine Citation:
PMID:  21182313     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cinacalcet (CIN) is a calcimimetic drug, which contains a naphthalene chromophore and binds almost quantitatively to human serum albumin (HSA). In the present work, the excited states of CIN have been characterized in order to obtain relevant information about complexation of CIN with HSA. The fluorescence spectrum in acetonitrile, at λ(exc) = 290 nm, displayed two bands with maxima at 332 and 439 nm, assigned to the monomer and exciplex emission. Upon protonation of the amino group, the exciplex band disappeared, with a concomitant increase of the monomer emission intensity. Time-resolved fluorescence evidenced an intramolecular dynamic quenching, attributed to exciplex formation and/or photoinduced electron transfer, in agreement with the favorable thermodynamics predicted by the Rehm-Weller equations. Diffusion controlled dynamic quenching of CINH(+) fluorescence by oxygen was observed. The emission properties in PBS were similar to those obtained for CINH(+) in acetonitrile. Laser flash photolysis (LFP) of CIN and CINH(+) in acetonitrile/N(2), at λ(exc) = 308 nm, gave rise to the naphthalene-like triplet excited states, with maxima at 420 nm and lifetimes of 4 and 7 μs; they were efficiently quenched by oxygen. No significant singlet excited state interaction was observed in CINH(+)/HSA complexes, as revealed by the emission spectra, which were roughly explained taking into account the relative contributions of drug and protein in the absorption spectra. Upon LFP of the complexes, triplet excited states were generated; the decays monitored at 420 nm were satisfactorily fitted using a function containing two monoexponential terms, corresponding to a short-lived (τ(1) = 8 μs) and a long-lived (τ(2) = 37 μs) component. This indicates that the drug is incorporated into two different binding sites of HSA. Despite the long triplet lifetimes of the CINH(+)/HSA complexes, the rate constant of quenching by oxygen was found to be 2 orders of magnitude lower than that determined in acetonitrile, which can be attributed to the relative slower diffusion rates in this microheterogeneous system. Therefore, the protein microenvironment protects cinacalcet from attack by oxygen; this prevents the phototoxic effects caused by formation of singlet oxygen and results in an enhanced photosafety of the drug.
Authors:
Edurne Nuin; Inmaculada Andreu; M José Torres; M Consuelo Jiménez; Miguel A Miranda
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-12-23
Journal Detail:
Title:  The journal of physical chemistry. B     Volume:  115     ISSN:  1520-5207     ISO Abbreviation:  J Phys Chem B     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-02-03     Completed Date:  2011-05-23     Revised Date:  2013-05-30    
Medline Journal Info:
Nlm Unique ID:  101157530     Medline TA:  J Phys Chem B     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1158-64     Citation Subset:  IM    
Affiliation:
Departamento de Química-Instituto de Tecnología Química (UPV-CSIC), Universidad Politécnica de Valencia, Valencia, Spain.
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MeSH Terms
Descriptor/Qualifier:
Humans
Naphthalenes / chemistry*
Photolysis
Serum Albumin / chemistry*
Singlet Oxygen / metabolism
Spectrophotometry, Ultraviolet
Chemical
Reg. No./Substance:
0/Naphthalenes; 0/Serum Albumin; 17778-80-2/Singlet Oxygen; UAZ6V7728S/cinacalcet

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