Gross A S, Eser C, Mikus G, Eichelbaum M
Dr. Margarete Fischer-Bosch-Institut für Klinische Pharmakologie, Stuttgart, Germany.
Chirality. 1993;5(6):414-8. doi: 10.1002/chir.530050604.
The protein binding of the enantiomers of gallopamil has been investigated in solutions of human serum albumin, alpha 1-acid glycoprotein and serum. Over the range of concentrations attained after oral gallopamil administration, the binding of both enantiomers to albumin, alpha 1-acid glycoprotein, and serum proteins was independent of gallopamil concentration. The binding to both human serum albumin (40 g/liter) [range of fraction bound (fb) R: 0.624 to 0.699; S: 0.502 to 0.605] and alpha 1-acid glycoprotein (0.5 g/liter) (range of fb R: 0.530 to 0.718; S: 0.502 to 0.620) was stereoselective, favoring the (R)-enantiomer (predialysis gallopamil concentrations 2.5 to 10,000 ng/ml). When the enantiomers (predialysis gallopamil concentration 10 ng/ml) were studied separately in drug-free serum samples from six healthy volunteers the fraction of (S)-gallopamil bound (fb: 0.943 +/- 0.016) was lower (P < 0.05) than that of (R)-gallopamil (fb: 0.960 +/- 0.010). The serum protein binding of both (R)- and (S)-gallopamil was unaffected by their optical antipodes (fb R: 0.963 +/- 0.011; S: 0.948 +/- 0.015) indicating that at therapeutic concentrations a protein binding enantiomer-enantiomer interaction does not occur. The protein binding of (R)- and (S)-gallopamil ex vivo 2 h after single dose oral administration of 50 mg pseudoracemic gallopamil (fb R: 0.960 +/- 0.010: predialysis [R] 6.9 to 35.3 ng/ml; S: 0.943 +/- 0.016: predialysis [S] 9.5 to 30.7 ng/ml) was comparable to that observed in vitro in drug-free serum. Gallopamil metabolites formed during first-pass following oral administration, therefore, do not influence the protein binding of (R)- or (S)-gallopamil.
已在人血清白蛋白、α1-酸性糖蛋白和血清溶液中研究了加洛帕米对映体的蛋白质结合情况。在口服加洛帕米后达到的浓度范围内，两种对映体与白蛋白、α1-酸性糖蛋白和血清蛋白的结合均与加洛帕米浓度无关。与人类血清白蛋白（40 g/升）[结合分数（fb）范围：R：0.624至0.699；S：0.502至0.605]和α1-酸性糖蛋白（0.5 g/升）（fb范围：R：0.530至0.718；S：0.502至0.620）的结合具有立体选择性，更倾向于（R）-对映体（透析前加洛帕米浓度为2.5至10,000 ng/ml）。当在来自六名健康志愿者的无药物血清样本中分别研究对映体（透析前加洛帕米浓度为10 ng/ml）时，（S）-加洛帕米的结合分数（fb：0.943±0.016）低于（R）-加洛帕米（fb：0.960±0.010）（P<0.05）。（R）-和（S）-加洛帕米的血清蛋白结合均不受其旋光对映体的影响（fb R：0.963±0.011；S：0.948±0.015），这表明在治疗浓度下不存在蛋白质结合对映体-对映体相互作用。单次口服50 mg消旋加洛帕米2小时后，（R）-和（S）-加洛帕米在体内的蛋白结合（fb R：0.960±0.010：透析前[R]为6.9至35.3 ng/ml；S：0.943±0.016：透析前[S]为9.5至30.7 ng/ml）与在无药物血清中的体外观察结果相当。因此，口服给药首过代谢过程中形成的加洛帕米代谢产物不会影响（R）-或（S）-加洛帕米的蛋白结合。
