Wang H P, Lu H H, Lee J S, Cheng C Y, Mah J R, Ku C Y, Hsu W, Yen C F, Lin C J, Kuo H S
School of Pharmacy, College of Medicine, National Taiwan University, Taipei, R.O.C.
J Pharm Pharmacol. 1996 Mar;48(3):270-6. doi: 10.1111/j.2042-7158.1996.tb05915.x.
Two dipeptide mimetic prodrugs, 1 and 2, and two tripeptide mimetic prodrugs, 3 and 4, of L-alpha-methyldopa were evaluated for intestinal absorption by in-situ single pass rat jejunal perfusion studies and by in-vitro uptake experiments in brush-border membrane vesicles (BBMVs) prepared from rat intestine. In the perfusion studies, compound 1 demonstrated a 3.5-fold increase in permeability (Pm* = 2.27) as compared with that of alpha-methyldopa (Pm* = 0.65), indicating that this prodrug was better absorbed in the intestine than its parent drug. Other prodrugs showed no significant improvement in intestinal permeability. The results correlated with the results of BBMV uptake studies. In the presence of an inward proton gradient, compound 1 showed Michaelis-Menton saturable kinetics of BBMV uptake with a low value of K(m) (0.06 +/- 0.13 mM) and a high value of Vmax/K(m)(36.38 nmol (mg protein)-1/30s mM-1) at a low concentration range and a linear uptake at high concentrations with Kd = 0.14 +/- 0.02 mM. Compounds 2 and 3 were mainly taken up in BBMVs via passive diffusion. Compound 4 was taken up in BBMVs basically via the carrier-mediated transport system, while the rate of uptake was much lower than that of compound 1. The uptake of compounds 1 and 4 was significantly inhibited by dipeptides L-Gly-L-Pro and L-Gly-L-Phe, and cephradine, a beta-lactam known to be transported via the dipeptide carrier system, indicating that both compounds were taken up in BBMVs via the H(+)-coupled dipeptide-mediated transport system. In contrast to the complicated uptake profile of alpha-methyldopa, the higher rate of BBMV uptake with less variation demonstrated on compound 1 suggested that the attached nonessential amino acid moiety, D-phenylglycine, is a feasible delivery tool in carrying the parent drug through the intestine.
通过大鼠空肠原位单通道灌注研究以及在由大鼠肠道制备的刷状缘膜囊泡（BBMVs）中进行的体外摄取实验，对L-α-甲基多巴的两种二肽模拟前药（1和2）以及两种三肽模拟前药（3和4）的肠道吸收情况进行了评估。在灌注研究中，与α-甲基多巴（Pm* = 0.65）相比，化合物1的渗透性增加了3.5倍（Pm* = 2.27），表明该前药在肠道中的吸收优于其母体药物。其他前药在肠道渗透性方面未显示出显著改善。结果与BBMV摄取研究的结果相关。在存在内向质子梯度的情况下，化合物1在低浓度范围内显示出BBMV摄取的米氏饱和动力学，K(m)值较低（0.06±0.13 mM），Vmax/K(m)值较高（36.38 nmol（mg蛋白质）-1/30s mM-1），在高浓度下呈线性摄取，Kd = 0.14±0.02 mM。化合物2和3主要通过被动扩散被摄取到BBMVs中。化合物4基本上通过载体介导的转运系统被摄取到BBMVs中，但其摄取速率远低于化合物1。化合物1和4的摄取受到二肽L-Gly-L-Pro和L-Gly-L-Phe以及头孢拉定（一种已知通过二肽载体系统转运的β-内酰胺）的显著抑制，表明这两种化合物都是通过H(+)-偶联二肽介导的转运系统被摄取到BBMVs中的。与α-甲基多巴复杂的摄取情况相反，化合物1显示出较高的BBMV摄取速率且变化较小，这表明所连接的非必需氨基酸部分D-苯甘氨酸是携带母体药物通过肠道的一种可行的递送工具。
