Distribution to the Brain and Protein Binding of 3′and 5-Substituted 2′,3′-Dideoxyuridine Derivatives, Studied by Microdialysis

Abstract

SummaryThe aim of this study was to investigate a series of 3' and 5-substituted 2',3' -dideoxyuridine derivatives (ddUD) with respect to plasma protein binding, halflife and distribution across the blood-brain barrier in the rat. The microdialysis technique was used to study protein binding in human plasma (in vitro), and to sample the extracellular space of rats with microdialysis probes implanted into the striatum of the brain and the gastrocnemic muscle (in vivo). The compounds were analysed by HPLC with UV-detection. The octanol/water partition coefficients of the dduD varied from 0.08-0.84. The protein binding of the ddUDswas approximately 80%. After s.c. administration (25 or 50 mg kg-1 ), the brain and muscle extracellular levels differed; brain levels were 0.18-0.36 o] peripheral (muscle) concentrations. A multivariate analysis, which included data on zidovudine, alovudine and thymidine, demonstrated a relationship between the physicochemical and some of the phormacokinetic properties of uridine analogues. The analysis shows that half-life and protein binding increases with decreasing pK a . However, penetration to the brain is not correlated with the partition into octano!. It is concluded that the transport to the brain is not primarily dependent upon passive diffusion over a lipophilic barrier but, rather, to other chemical properties of the dduDs. This is suggestive of a specific transport mechanism, e.g. the thymidine carrier.

Pharmacokinetics and metabolism of the novel synthetic C‐nucleoside, 1‐(2‐deoxy‐β‐D‐ribofuranosyl)‐2,4‐difluoro‐ 5‐iodobenzene: a potential mimic of 5‐iodo‐2′‐deoxyuridine

“…This is in contrast to thymidine and 3 0 -azido-3 0 -deoxythymidine (AZT), which are less lipophilic and are far less protein bound (22 and 25%, respectively) [16][17][18].…”

“…Aliquots (50 ml) of these stock solutions were removed at specified time intervals (0.5, 1, 1.5, 2, 4,6,8,16,24,48,72,96, 120 h), and analyzed by quantitative HPLC. To determine stability in plasma, aliquots (10 ml) of a 1 mM solution of 5-IDFPdR in water were added to rat plasma (90 ml) to produce a 100 mM solution that was incubated at 378C in a water bath.…”

A new chitosan–thymine conjugate: Synthesis, characterization and biological activity

“…We have recently demonstrated that chitosan-chloroquinoline conjugate has also potent antimicrobial activity [19]. Several previous studies have synthesized various thymine derivatives and reported potent anti-cancer effect [20][21][22][23]. More recently, Manna et al found that, modification of hyaluronic acid with thymine, by the LBL process, imparted them an anticancer activity [16].…”

Michael Addition of Pyrimidine with Disaccharide Acrylates Catalyzed in Organic Medium with Lipase M from Mucor javanicus

“…But, to our best knowledge, Michael addition of pyrimidine with disaccharide acrylate catalyzed by lipase M from Mucor javanicus in organic medium has not been demonstrated. In this paper, we report a lipase M from Mucor javanicus-catalyzed Michael addition of sugarcontaining substrate for synthesis of pyrimidine derivatives containing a branched sugar which may possess potential antitumor and antivirus activities (Fedorov et al 1999, Borg et al 1997.…”