Evasion of P-gp mediated cellular efflux and permeability enhancement of HIV-protease inhibitor saquinavir by prodrug modification
Evasion of P-gp mediated cellular efflux and permeability enhancement of HIV-protease inhibitor saquinavir by prodrug modification
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DOI：
10.1016/j.ijpharm.2005.06.017
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发表时间：
2005-10-13
影响因子：
5.8
通讯作者：
Mitra, AK
中科院分区：
文献类型：
--
作者：
Jain, R;Agarwal, S;Mitra, AK
p -糖蛋白（P-gp）是一种外排泵，负责限制HIV蛋白酶抑制剂沙奎那韦（SQV）的口服生物利用度、组织渗透和增加代谢。本研究的目的是探讨SQV的前药衍生为靶向肽转运体的新型二肽前药val - val -沙奎那韦（Val-Val-SQV）和gy - val -沙奎那韦（gy - val -SQV）是否可以增强沙奎那韦的细胞通透性并调节P-gp介导的外排。采用MDCKII-MDR1细胞系，在37℃下分别进行10 min和3h的摄取和转运研究。以[H-3]利托那韦和[H-3]红霉素作为模型P-gp底物，在存在抑制浓度的SQV及其肽前药的情况下进行摄取。对生长在膜插入物上的MDCKII-MDR1细胞进行了双向转运研究。在75 μ M SQV存在时，MDCKII-MDR1细胞对[H-3]红霉素的摄取增加了4倍。然而，等摩尔浓度的Val-Val-SQV和Gly-Val-SQV仅使[3 H]红霉素摄取增加2.5倍。在SQV前药的存在下，观察到模型肽转运蛋白底物[H-3]甘氨酸- sarcos （Gly-Sar）的浓度依赖性抑制。与使用SQV的研究相比，Val-Val-SQV和gy - val -SQV的经上皮转运研究显示吸收通量增强，分泌通量减少。这些结果很可能是由于P-gp减少了SQV二肽前药的外排。肽前药衍生化是一种令人兴奋的策略，可以改善SQV的肠道吸收和口服生物利用度(c) 2005 Elsevier B.V.。
P-glycoprotein (P-gp) is an efflux pump responsible for limiting oral bioavailability, tissue penetration and increasing metabolism of the HIV protease inhibitor saquinavir (SQV). The objective of this study is to investigate whether prodrug derivatization of SQV to novel dipeptide prodrugs Val-Val-saquinavir (Val-Val-SQV) and Gly-Val-saquinavir (Gly-Val-SQV) targeting peptide transporters can enhance cellular permeability of saquinavir and modulate P-gp mediated efflux. Uptake and transport studies were conducted employing MDCKII-MDR1 cell line at 37 degrees C for 10 min and 3h, respectively. Uptake of [H-3]ritonavir and [H-3]erythromycin, utilized as model P-gp substrates, was carried out in the presence of inhibitory concentration of SQV and its peptide prodrugs. Bidirectional transport studies were conducted on MDCKII-MDR1 cells grown over membrane inserts.Uptake of [H-3]erythromycin by MDCKII-MDR1 cells exhibited a four-fold increase in the presence of 75 mu M SQV However, equimolar concentrations of Val-Val-SQV and Gly-Val-SQV showed only 2.5-fold increase in [3 H]erythromycin uptake. Concentration dependent inhibition of [H-3]glycylsarcosine (Gly-Sar), a model peptide transporter substrate, was observed in the presence of SQV prodrugs. Transepithelial transport studies of Val-Val-SQV and Gly-Val-SQV exhibited an enhanced absorptive flux and reduced secretory flux relative to studies employing SQV These results are very likely due to decreased efflux of SQV dipeptide prodrugs by P-gp. Peptide prodrug derivatization constitutes an exciting strategy to improve intestinal absorption and oral bioavailability of SQV (c) 2005 Elsevier B.V. All rights reserved.