کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1361041 | 981456 | 2008 | 14 صفحه PDF | دانلود رایگان |

Human plasma protein binding of six antimalarial agents of quinoline and acridine types was investigated by using spectroscopic techniques, affinity chromatography, ultrafiltration and HPLC methods. Induced circular dichroism (ICD) spectra showed binding of amodiaquine (AMQ), primaquine (PRQ), tafenoquine (TFQ), and quinacrine (QR) to α1-acid glycoprotein (AAG), the serum level of which greatly increases in Plasmodium infections. Association constant (Ka) values of about 105–106 M−1 could be determined. Analysis of the ICD and UV spectra of the drug–AAG complexes suggested the inclusion of the ligands into the central hydrophobic cavity of the protein. Using the purified forms of the two main genetic variants of AAG, ICD data indicated the selective binding of AMQ and PRQ to the ‘F1/S’, while QR to the ‘A’ variant. Results of fluorescence experiments supported the AAG binding of these drugs and provided further insights into the binding details of TFQ and QR. Fluorescence and CD displacement experiments showed the high-affinity AAG binding of mefloquine (Ka ≈ 106 M−1). For this drug, inverse binding stereoselectivities were found with the ‘F1/S’ and ‘A’ genetic variants of AAG. HSA association constants estimated from affinity chromatography results lag behind (103–105 M−1) the similar values derived for AAG. In case of chloroquine, no significant binding interaction was found either with AAG or HSA. Pharmacological aspects of the results are discussed.
The acute-phase component serum α1-acid glycoprotein is an important contributor in plasma protein binding of antimalarial agents of quinoline and acridine type.Figure optionsDownload as PowerPoint slide
Journal: Bioorganic & Medicinal Chemistry - Volume 16, Issue 7, 1 April 2008, Pages 3759–3772