Vitreal Pharmacokinetics of Peptide-Transporter-Targeted Prodrugs of Ganciclovir in Conscious Animals
Vitreal Pharmacokinetics of Peptide-Transporter-Targeted Prodrugs of Ganciclovir in Conscious Animals
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DOI：
10.1089/jop.2009.0123
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发表时间：
2010-06-01
影响因子：
2.3
通讯作者：
Mitra, Ashim K.
中科院分区：
文献类型：
--
作者：
Janoria, Kumar G.;Boddu, Sai H. S.;Mitra, Ashim K.
目的：采用眼微透析技术建立清醒家兔模型，研究更昔洛韦（GCV）二肽单酯前体药物在玻璃体中的药代动力学，并与麻醉家兔模型的结果进行比较。采用具有永久植入探针的清醒动物眼微透析技术来描述玻璃体内给药后GCV、L-缬氨酸-GCV（Val-GCV）和二肽单酯GCV前药[Val-瓦尔和L-甘氨酸-瓦尔（Gly-瓦尔）]的药代动力学。本工作采用清醒模型评价玻璃体药代动力学参数，并将结果与先前发表的麻醉动物的数据进行比较，从而证明麻醉对GCV的二肽前药的玻璃体处置的影响。结果表明，相对于麻醉模型，清醒动物中所有4种化合物的曲线下面积（AUC）、清除率和最后测量的血浆浓度（C-last）均显著改变，而平均停留时间（MRT）显著缩短。然而，从Gly-Val-GCV和Val-Val-GCV再生的Val-GCV和GCV的AUC被发现是不变的，这表明在清醒animal.Conclusion：这项研究首次描绘了清醒动物中的GCV前药的玻璃体药代动力学，并与麻醉动物的数据进行比较。在清醒动物模型的情况下，获得较低的玻璃体暴露水平;然而，消除率不受麻醉的影响。
Purpose: To delineate the vitreal pharmacokinetics of dipeptide monoester prodrugs of ganciclovir (GCV) with conscious rabbit model using ocular microdialysis and to compare with published results from anesthetized model.Methods: New Zealand albino male rabbit was selected as the animal model. Conscious animal ocular microdialysis technique with permanently implanted probes was employed to delineate the pharmacokinetics of GCV, L-valine-GCV (Val-GCV), and dipeptide monoester GCV prodrugs [Val-Val and L-glycine-Val (Gly-Val)] after intravitreal administration.Results: This work employs conscious model to evaluate vitreal pharmacokinetic parameters and compares the results with previously published data from anesthetized animal, thereby demonstrating the effect of anesthesia on the vitreal disposition of dipeptide prodrugs of GCV. Results have revealed that area under curve (AUC), clearance, and last measured plasma concentration (C-last) for all 4 compounds were significantly altered in a conscious animal relative to the anesthetized model, while mean residence time (MRT) was significantly reduced. However, the AUCs of regenerated Val-GCV and GCV from Gly-Val-GCV and Val-Val-GCV were found to be unchanged, suggesting higher ocular metabolism in conscious animals.Conclusion: This study for the first time delineates the vitreal pharmacokinetics of a GCV prodrug in conscious animals and compares the data with anesthetized animals. Lower vitreal exposure levels were obtained in case of conscious animal model; however, the elimination rates were not influenced by anesthesia.