Pharmacokinetics of amino acid ester prodrugs of acyclovir after oral administration: Interaction with the transporters on Caco-2 cells
Pharmacokinetics of amino acid ester prodrugs of acyclovir after oral administration: Interaction with the transporters on Caco-2 cells
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DOI：
10.1016/j.ijpharm.2008.06.018
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发表时间：
2008-10-01
影响因子：
5.8
通讯作者：
Mitra, Ashim K.
中科院分区：
文献类型：
--
作者：
Katragadda, Suresh;Jain, Ritesh;Mitra, Ashim K.
研究了阿昔洛韦（ACV）氨基酸前体药物在大鼠体内的吸收情况。评价了前药L-丙氨酸-ACV（AACV）、L-丝氨酸（SACV）、L-异亮氨酸-ACV（IACV）、γ-谷氨酸-ACV（EACV）和L-缬氨酸-ACV（VACV）在各种组织中的稳定性。研究了这些前药与Caco-2细胞上转运蛋白的相互作用。这些前药的体内全身生物利用度显示出对各种氨基酸转运蛋白以及Caco-2细胞上的肽转运蛋白的亲和力。在稳定性方面，与其他前药相比，EACV最稳定，尤其是在肝匀浆中。口服吸收研究。ACV和AACV显示高的末端消除速率常数（λ（z））。SACV和VACV的曲线下面积（AUC）值比ACV增加约5倍（p < 0.05）。观察到SACV在血浆中的C-max（T）（最大浓度）为39 +/- 22 μ M，比VACV好2倍，比ACV好15倍。观察到SACV的C-last（T）（最后时间点的浓度）在血浆中为0.18 +/-0.06 μ M，比VACV好两倍，比ACV好三倍。ACV的氨基酸酯前药以不同的量（C-max）吸收，并以不同的速率（λ（z））消除，从而导致不同的程度（AUC）。氨基酸酯前药SACV由于其增强的稳定性、较高的AUC和较好的最后时间点浓度，似乎是口服治疗疱疹感染的有希望的候选者。(C)2008 Elsevier B. V.保留所有权利。
In vivo systemic absorption of the amino acid prodrugs of acyclovir (ACV) after oral administration was evaluated in rats. Stability of the prodrugs, L-alanine-ACV (AACV), L-serine (SACV), L-isoleucine-ACV (IACV), gamma-glutamate-ACV (EACV) and L-valine-ACV (VACV) was evaluated in various tissues. Interaction of these prodrugs with the transporters on Caco-2 cells studied. In vivo systemic bioavailability of these prodrugs showed affinity towards various amino acid transporters as well as the peptide transporter on the Caco-2 cells. In terms of stability, EACV was most enzymatically stable compared to other prodrugs especially in liver homogenate. In oral absorption studies. ACV and AACV showed high terminal elimination rate constants (lambda(z)). SACV and VACV exhibited approximately five-fold increase in area under the curve (AUC) values relative to ACV (p < 0.05). C-max(T) (maximum concentration) of SACV was observed to be 39 +/- 22 mu M in plasma which is 2 times better than VACV and 15 times better than ACV. C-last(T) (concentration at the last time point) of SACV was observed to be 0.18 +/- 0.06 mu M in plasma which is two times better than VACV and three times better than ACV. Amino acid ester prodrugs of ACV were absorbed at varying amounts (C-max) and eliminated at varying rates (lambda(z)) thereby leading to varying extents (AUC). The amino acid ester prodrug SACV owing to its enhanced stability, higher AUC and better concentration at last time point seems to be a promising candidate for the oral treatment of herpes infections. (C) 2008 Elsevier B.V. All rights reserved.