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Synthesis, In Vitro and In Vivo Release Kinetics, and Anti‐HIV Activity of A Sustained‐Release Prodrug (mPEG‐AZT) of 3′‐Azido‐3′‐deoxythymidine (AZT, Zidovudine)
Author(s) -
Li Wenjun,
Chang Yu,
Zhan Peng,
Zhang Na,
Liu Xinyong,
Pannecouque Christophe,
De Clercq Erik
Publication year - 2010
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201000352
Subject(s) - prodrug , zidovudine , conjugate , chemistry , in vitro , ethylene glycol , pharmacokinetics , nuclear chemistry , peg ratio , in vivo , polyethylene glycol , fourier transform infrared spectroscopy , chromatography , pharmacology , combinatorial chemistry , biochemistry , human immunodeficiency virus (hiv) , organic chemistry , medicine , biology , mathematical analysis , mathematics , microbiology and biotechnology , finance , viral disease , economics , physics , quantum mechanics , family medicine
A poly(ethylene glycol) (PEG) conjugate of 3′‐azido‐3′‐ deoxythymidine (AZT, zidovudine) was designed and synthesized as a novel sustained‐release prodrug. In the synthetic process, a succinate diester spacer was used to covalently couple AZT with methoxy poly(ethylene glycol) (mPEG; MW=2000). The conjugate was characterized by Fourier transform infrared (FTIR) and NMR spectroscopies and matrix‐assisted laser desorption/ionization‐time of flight (MALDI‐TOF) mass spectrometry (MS). The in vitro release was determined in hydrochloride (HCl) solution (pH 1.2) and phosphate‐buffered solution (PBS; pH 6.8), which showed the release rate of AZT from the conjugate was slower than that from the free drug, suggesting its possible increased retention in gastrointestinal conditions. Pharmacokinetic properties were evaluated experimentally by oral administration in mice. Compared to free AZT, the absorption half‐life ( t $_{{1\over2}}$ ka ) and elimination half life ( t $_{{1\over2}}$ β ) of AZT released from the conjugate were both extended to 0.51±0.03 h ( p <0.01) and 2.94±0.24 h ( p <0.01), respectively. Evaluation of the in vitro anti‐HIV activities showed mPEG‐AZT exhibited good inhibition of HIV‐1, with an EC 50 value of 0.0634 μ M , but it is lower than that of free AZT. These results show that the conjugate is capable of releasing the parent drug in a sustained profile, potentially providing a feasible alternative to oral administration of AZT in a clinical setting.