Savolainen J, Leppanen J, Forsberg M, Taipale H, Nevalainen T, Huuskonen J, Gynther J, Mannisto P T, Jarvinen T
Department of Pharmaceutical Chemistry, University of Kuopio, Finland.
Life Sci. 2000;67(2):205-16. doi: 10.1016/s0024-3205(00)00615-9.
Entacapone has a relatively low oral bioavailability which may, in part, be due to its low aqueous solubility at low pH and/or its hydrophilic character at neutral pH. Various novel N-alkyl and N,N-dialkyl carbamate esters of entacapone were synthesized as possible prodrugs of entacapone in order to increase its aqueous solubility at an acidic pH and to increase its lipophilicity at neutral pH. Oral bioavailability of entacapone and selected carbamate esters were investigated in rats. Both N-alkyl and N,N-dialkyl carbamate esters were relatively stable against chemical hydrolysis at pH 7.4 (t1/2 = 14.9-20.7 h), but hydrolyzed rapidly (t1/2 = 0.8-2.7 h) in human serum. However, in contrast to N-alkyl carbamates, N,N-dialkyl carbamates did not release entacapone in in vitro enzymatic hydrolysis (human serum) studies. N-Alkyl carbamates, 2a-c, showed increased aqueous solubility at pH 7.4, of which 2a and 2c also show increased aqueous solubility at pH 5.0, compared to entacapone. In addition to increased aqueous solubility, 2c showed increased lipophilicity at pH 7.4. However, two N-alkyl carbamates of entacapone did not increase the oral bioavailability of the parent drug in rats. Thus, it can be concluded that the relatively low lipophilicity of entacapone is not the cause of its low bioavailability.
恩他卡朋的口服生物利用度相对较低，这可能部分归因于其在低pH值下的低水溶性和/或在中性pH值下的亲水性。合成了各种新型的恩他卡朋N-烷基和N,N-二烷基氨基甲酸酯作为恩他卡朋可能的前药，以提高其在酸性pH值下的水溶性并增加其在中性pH值下的亲脂性。在大鼠中研究了恩他卡朋和选定氨基甲酸酯的口服生物利用度。N-烷基和N,N-二烷基氨基甲酸酯在pH 7.4时对化学水解相对稳定（t1/2 = 14.9 - 20.7小时），但在人血清中迅速水解（t1/2 = 0.8 - 2.7小时）。然而，与N-烷基氨基甲酸酯不同，N,N-二烷基氨基甲酸酯在体外酶水解（人血清）研究中不释放恩他卡朋。N-烷基氨基甲酸酯2a - c在pH 7.4时显示出水溶性增加，其中2a和2c与恩他卡朋相比在pH 5.0时也显示出水溶性增加。除了水溶性增加外，2c在pH 7.4时显示出亲脂性增加。然而，恩他卡朋的两种N-烷基氨基甲酸酯并未提高母体药物在大鼠中的口服生物利用度。因此，可以得出结论，恩他卡朋相对较低的亲脂性不是其低生物利用度的原因。
