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Enantioselective plasma protein binding of propafenone: Mechanism, drug interaction, and species difference
Author(s) -
Hong Yanjun,
Tang Yihong,
Zeng Su
Publication year - 2009
Publication title -
chirality
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.43
H-Index - 77
eISSN - 1520-636X
pISSN - 0899-0042
DOI - 10.1002/chir.20666
Subject(s) - chemistry , enantiomer , human serum albumin , stereoselectivity , digitoxin , stereochemistry , nitrendipine , binding site , plasma protein binding , enantioselective synthesis , chromatography , biochemistry , calcium , digoxin , organic chemistry , heart failure , medicine , catalysis
The interaction of propafenone (PPF) enantiomers with human plasma, human serum albumin (HSA), α 1 ‐acid glycoprotein (AGP), as well as with plasma from rat, rabbit, and cow was investigated using indirect chiral high performance liquid chromatography (HPLC) and ultrafiltration techniques. The stronger binding of the S ‐PPF found in human plasma was due to AGP. Two classes of binding sites in AGP were identified: one with high‐affinity and small binding capacity ( K 1(S) = 7.65 × 10 6 M −1 , n 1(S) = 0.50; K 1(R) = 2.81 × 10 6 M −1 , n 1(R) = 0.46), which revealed stereoselectivity; the other with low‐affinity and high‐binding capacity ( n 2(S) K 2(S) = 9.95 × 10 3 M −1 ; n 2(R) K 2(R) = 9.74 × 10 3 M −1 ). The binding to HSA was found to be weak and not enantioselective ( nK S = 2.08 × 10 3 M −1 , nK R = 2.05 × 10 3 M −1 ). The interaction between enantiomers observed in human plasma was confirmed as a competitive type interacting at the high‐affinity site in AGP. The binding mode of both enantiomers with AGP was mainly hydrophobic bond. PPF enantiomers had higher‐binding affinity for the F‐S variant of human AGP. Drug‐drug binding interaction studies showed that verapamil, diazepam, nifedipine, furosemide, nitrendipine, and nimodipine did not affect the binding of PPF enantiomers except quinidine and aprindine at the therapeutic concentration. Comparative studies indicated considerable species‐dependent binding stereoselectivity between plasma of the four species investigated. Chirality, 2009. © 2008 Wiley‐Liss, Inc.