Didanosine ester prodrugs: Synthesis, albumin binding properties and pharmacokinetic studies in rats

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• 作者：Sverre Hø ; yem ; Skjalg Bruheim ; Gunhild M&#xe6 ; l ; smo ; Marius St ; al ; Dag Erlend Olberg ; Bjarne Brudeli ; Anders Å ; sberg ; Jo Klaveness ; P&#xe5 ; l Rongved
• 关键词：Albumin ; Bioanalysis ; In vitro/in vivo correlations (IVIVC) ; Pharmacokinetics ; Prodrugs ; Protein binding ; Stability ; Synthesis
• 刊名：European Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：October 2009
• 年：2009
• 卷：44
• 期：10
• 页码：3874-3879
• 全文大小：286 K

文摘

Three half-ester derivatives 10–12 of 5′-O-2′,3′-dideoxydidanosine (DDI, 1) have been synthesized. The compounds exhibited excellent correlation between partition coefficients Log P and relative in vitro bovine serum albumin binding. Using high-performance liquid chromatography–mass spectrometry (LC–MS), DDI (1) was quantitatively determined in rat plasma after intravenous injection of the azelaic acid monoester derivative (11) of DDI. The pharmacokinetic data obtained for DDI were consistent with literature. The pharmacokinetic profile of 11 showed no significant difference in AUC_0–360 or curve shape compared to the parent drug DDI (1). The data indicate that the prodrug was converted to DDI within minutes after administration. High relative protein binding in vitro holds a promise for validity of the concept using more stable linker bonds.