School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
Bioorg Chem. 2018 Dec;81:494-503. doi: 10.1016/j.bioorg.2018.09.018. Epub 2018 Sep 11.
Alkyl ester prodrugs are well known to be bioconverted by carboxylesterases, particularly in rodents' by first-pass metabolism in the systemic circulation and liver. However, the bioconversion of structurally more complex esters with polar functional groups is less well understood, especially in humans. Therefore, it is not clear if ester prodrugs can be utilized for targeted drug delivery. In the present study a brain-targeted ester prodrug (1) of ketoprofen, utilizing the l-type amino acid transporter 1 (LAT1) was prepared and the enzymes involved in its metabolism in human plasma and liver S9 subcellular fraction as well as rat brain S9 fraction were identified. Furthermore, species differences among mouse, rat and human plasma and liver S9 fraction were compared. The results showed that bioconversion of the ester prodrug was much faster in mouse plasma compared to human, while it's half-life in rat plasma was closer to the one of human. Moreover, both rodent species showed more efficient bioconversion in the liver S9 fractions compared to human and relatively efficient bioconversion in the brain S9 fractions. More specifically, butyrylcholinesterase (BChE) and paraoxygenase 1 (PON1) were the main hydrolyzing enzymes of the prodrug 1 in human plasma, while carboxylesterases 1 and 2 (CES1 and CES2) as well as PONs were the main bioconverting enzymes in human liver S9 fractions. In rat brain S9 fraction, acetylcholinesterase (AChE) was hydrolyzing the prodrug 1, although also other unidentified metal-and pH-dependent enzyme(s) were recognized to be participating to the total bioconversion of the compound 1 in the brain.
烷酯前药众所周知可被羧酸酯酶生物转化，尤其是在啮齿动物的全身循环和肝脏的首过代谢中。然而，对于具有极性官能团的结构更为复杂的酯的生物转化了解较少，特别是在人类中。因此，尚不清楚酯前药是否可用于靶向药物递送。在本研究中，制备了酮洛芬的脑靶向酯前药（1），利用 L 型氨基酸转运蛋白 1（LAT1），并鉴定了其在人血浆和肝 S9 亚细胞部分以及大鼠脑 S9 部分中的代谢相关酶。此外，还比较了小鼠、大鼠和人血浆和肝 S9 部分之间的种属差异。结果表明，与人类相比，该酯前药在小鼠血浆中的生物转化速度更快，而在大鼠血浆中的半衰期更接近人类。此外，与人类相比，两种啮齿动物的肝 S9 部分的生物转化效率更高，而脑 S9 部分的生物转化效率相对较高。更具体地说，丁酰胆碱酯酶（BChE）和对氧磷酶 1（PON1）是 1 在前药在人血浆中的主要水解酶，而羧酸酯酶 1 和 2（CES1 和 CES2）以及 PONs 是在人肝 S9 部分中的主要生物转化酶。在大鼠脑 S9 部分中，乙酰胆碱酯酶（AChE）水解前药 1，尽管还识别出其他未鉴定的金属和 pH 依赖性酶参与化合物 1 在脑中的总生物转化。
