Stereoselective binding of doxazosin enantiomers to plasma proteins from rats, dogs and humans in vitro.
OBJECTIVE
(±)Doxazosin is a long-lasting inhibitor of α1-adrenoceptors that is widely used to treat benign prostatic hyperplasia and lower urinary tract symptoms. In this study we investigated the stereoselective binding of doxazosin enantiomers to the plasma proteins of rats, dogs and humans in vitro.


METHODS
Human, dog and rat plasma were prepared. Equilibrium dialysis was used to determine the plasma protein binding of each enantiomer in vitro. Chiral HPLC with fluorescence detection was used to measure the drug concentrations on each side of the dialysis membrane bag.


RESULTS
Both the enantiomers were highly bound to the plasma proteins of rats, dogs and humans [(-)doxazosin: 89.4%-94.3%; (+)doxazosin: 90.9%-95.4%]. (+)Doxazosin exhibited significantly higher protein binding capacities than (-)doxazosin in all the three species, and the difference in the bound concentration (Cb) between the two enantiomers was enhanced as their concentrations were increased. Although the percentage of the plasma protein binding in the dog plasma was significantly lower than that in the human plasma at 400 and 800 ng/mL, the corrected percentage of plasma protein binding was dog>human>rat.


CONCLUSIONS
(-)Doxazosin and (+)doxazosin show stereoselective plasma protein binding with a significant species difference among rats, dogs and humans.
1] Institute of Chinese Integrative Medicine, Hebei Medical University, Shijiazhuang 050071, China [2] Bethune International Peace Hospital, Shijiazhuang 050081, China.
Jia-an
JA
Sun
De-zhi
DZ
Kong
Ya-qin
YQ
Zhen
Qing
Q
Li
Wei
W
Zhang
Jiang-hua
JH
Zhang
Zhi-wei
ZW
Yin
Lei-ming
LM
Ren
D058668:Adrenergic alpha-1 Receptor Antagonists / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism*; D004285:Dogs; D017292:Doxazosin / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D011485:Protein Binding; D051381:Rats; D013237:Stereoisomerism
D058668:Adrenergic alpha-1 Receptor Antagonists; D001798:Blood Proteins; D017292:Doxazosin