Disposition kinetics of a dipeptide ester prodrug of acyclovir and its metabolites following intravenous and oral administrations in rat.

Ravi S Talluri, Ripal Gaudana, Sudharshan Hariharan, Ritesh Jain, Ashim K Mitra
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引用次数: 3

Abstract

The objective of this work was to study the disposition kinetics of valine-valine-acyclovir (VVACV), a dipeptide ester prodrug of acyclovir following intravenous and oral administrations in rat. A validated LC-MS/MS analytical method was developed for the analysis VVACV, Valine-Acyclovir (VACV), and Acyclovir (ACV) using a linear Ion Trap Quadrupole. ACV was administered orally for comparison purpose. In the VVACV group, both blood and urine samples and in the ACV group only blood samples were collected. All the samples were analyzed using LC-MS/MS. The LLOQ for ACV, VACV, and VVACV were 10, 10, and 50 ng/ml, respectively. Relevant pharmacokinetic parameters were obtained by non-compartmental analyses of data with WinNonlin. Following i.v. administration of VVACV, AUC(0-inf) (min*µM) values for VVACV, VACV, and ACV were 55.06, 106, and 466.96, respectively. The AUC obtained after oral administration of ACV was 178.8. However, following oral administration of VVACV, AUC(0-inf) values for VACV and ACV were 89.28 and 810.77, respectively. Thus the exposure of ACV obtained following oral administration of VVACV was almost 6-fold higher than ACV. This preclinical pharmacokinetic data revealed that VVACV has certainly improved the oral bioavailability of ACV and is an effective prodrug for oral delivery of ACV.

大鼠静脉和口服给药后阿昔洛韦二肽酯前药及其代谢产物的处置动力学。
本研究的目的是研究缬氨酸-缬氨酸-阿昔洛韦(valine-valine-acyclovir, VVACV),一种阿昔洛韦的二肽酯前药,在大鼠体内静脉和口服给药后的处置动力学。建立了线性离子阱四极杆色谱-质谱联用分析VVACV、缬氨酸-阿昔洛韦(VACV)和阿昔洛韦(ACV)的方法。口服ACV进行比较。VVACV组同时采集血液和尿液样本,ACV组仅采集血液样本。所有样品采用LC-MS/MS进行分析。ACV、VACV和VVACV的定量限分别为10、10和50 ng/ml。用WinNonlin软件对数据进行非区室分析,获得相关药动学参数。静脉注射VVACV后,VVACV、VACV和ACV的AUC(0-inf) (min*µM)值分别为55.06、106和466.96。口服ACV后AUC为178.8。然而,口服VVACV后,VACV和ACV的AUC(0-inf)值分别为89.28和810.77。因此,口服VVACV后获得的ACV暴露量几乎是ACV的6倍。这些临床前药代动力学数据表明,VVACV确实提高了ACV的口服生物利用度,是口服给药ACV的有效前药。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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