Stereoselective protein binding of tetrahydropalmatine enantiomers in human plasma, HSA, and AGP, but not in rat plasma.
Tetrahydropalmatine (THP) is one of the active alkaloid ingredients of Rhizoma Corydalis. THP has a chiral center, and the stereoselective pharmacokinetics and tissue distribution have been reported. The aim of the present article is to study the stereoselective protein binding of THP using equilibrium dialysis followed by HPLC-UV analysis. The results showed that THP stereoselectively binds to human serum albumin (HSA), alpha(1)-acid glycoprotein (AGP), and proteins in human plasma. The fraction binding of (+)-THP was significantly higher than that of (-)-THP, whereas such stereoselectivity was not found in rat plasma. The affinity of HSA and AGP to (+)-THP, expressed as nK(A), were 9.0 x 10(3) M(-1) and 2.34 x 10(5) M(-1), respectively, which were notablely higher than to (-)-THP, with the nK(A) of 3.4 x 10(3) M(-1) and 1.44 x 10(5) M(-1), respectively. The binding site of HSA for (-)-THP was Site I, whereas for (+)-THP was both Site I and Site II. The F1/S variants of AGP were proved to be the key variants (-)- and (+)-THP binding to both. Finally, the AGP binding drugs, such as mifepristone, were demonstrated to reduce the fraction binding of (-)- and (+)-THP with pure AGP (1 mg/ml) but did not affect the fraction binding of both (-)- and (+)-THP with proteins in human plasma. It can be concluded that protein binding of THP is species dependent and stereoselective, both HSA and AGP contribute to the stereoselective binding to THP enatiomers, and AGP binding drugs may not cause the drug-drug interaction on THP in healthy human plasma.
Sun
Dong-Li
DL
Department of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People's Republic of China.
Huang
Shan-Ding
SD
Wu
Pei-Sheng
PS
Li
Jia
J
Ye
Ya-Ju
YJ
Jiang
Hui-Di
HD
D000818:Animals; D001600:Berberine Alkaloids / Q000097:blood / Q000737:chemistry* / Q000378:metabolism*; D001667:Binding, Competitive; D004347:Drug Interactions; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology; D007099:Imipramine / Q000494:pharmacology; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D009961:Orosomucoid / Q000378:metabolism*; D010949:Plasma / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012709:Serum Albumin / Q000378:metabolism*; D013237:Stereoisomerism; D013379:Substrate Specificity; D014859:Warfarin / Q000494:pharmacology
D001600:Berberine Alkaloids; D009961:Orosomucoid; D012709:Serum Albumin; D015735:Mifepristone; C014215:tetrahydropalmatine; D014859:Warfarin; D007099:Imipramine; D007052:Ibuprofen