Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, USA.
J Pharm Sci. 2010 Mar;99(3):1574-81. doi: 10.1002/jps.21917.
LY354740 is a potent mGlu2/3 agonist with a limited oral bioavailability. Its alanyl prodrug, LY544344, showed high affinity to the intestinal peptide transporter PEPT1, and improved the oral bioavailability of LY354740 in various animal models. The aim of the present study was to investigate the mechanism of in vivo absorption of the dipeptidic prodrug LY544344. The permeabilities of LY544344 and LY354740 were examined in the rat in situ single-pass intestinal perfusion model. The intestinal absorptive flux of LY354740 was shown to be very low in comparison with LY544344. The absorptive flux of LY544344 could best be described by a Michaelis-Menten process in parallel with a linear process. The estimated parameters were: J(max) = 26.7 x 10(-5) micromol/(cm(2)-s), K(m) = 2.6 mM. The absorptive permeability of LY544344 was reduced to approximately 5% of control in the presence of excess Gly-Sar, a known PEPT1 substrate. Intracellular accumulation of LY354740 and LY544344, estimated postperfusion, showed high levels of LY354740 over LY544344 at all perfusate concentrations studied. However, there was a decline in the intracellular ratio of LY354740 to LY544344 at higher concentrations, suggesting that the metabolic activation to release LY354740 is saturable.
LY354740 是一种有效的 mGlu2/3 激动剂，但其口服生物利用度有限。其丙氨酰前药 LY544344 对肠道肽转运体 PEPT1 具有高亲和力，并提高了 LY354740 在各种动物模型中的口服生物利用度。本研究旨在探讨二肽前药 LY544344 的体内吸收机制。在大鼠在体单向肠灌流模型中检测了 LY544344 和 LY354740 的通透性。与 LY544344 相比，LY354740 的肠吸收通量非常低。LY544344 的吸收通量最好通过 Michaelis-Menten 过程与线性过程平行来描述。估计的参数为：J(max) = 26.7 x 10(-5) micromol/(cm(2)-s)，K(m) = 2.6 mM。在存在过量 Gly-Sar（已知的 PEPT1 底物）的情况下，LY544344 的吸收通透性降低至对照的约 5%。灌流后估计的 LY354740 和 LY544344 的细胞内积累显示，在所研究的所有灌流浓度下，LY354740 的水平均高于 LY544344。然而，在较高浓度下，LY354740 与 LY544344 的细胞内比值下降，表明代谢激活以释放 LY354740 是饱和的。
