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dc.contributor.advisorBreytenbach, J.C.
dc.contributor.advisorN'Da, D.D.
dc.contributor.advisorDu Plessis, J.
dc.contributor.authorLegoabe, Lesetja Jan
dc.descriptionThesis (Ph.D. (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2010.
dc.description.abstractCancer is reported to be one of the top ten leading causes of death worldwide and its treatment poses a number of challenges. Cytarabine is a deoxycytidine analogue commonly used in the treatment of haematological malignant diseases. Its clinical utility, however, is severely limited by its short plasma half-life due to the catabolic action of nucleoside deaminases. Due to the cell cycle (S-phase) specificity of cytarabine, a prolonged exposure of cells to cytarabine's cytotoxic concentrations is essential to achieve maximum activity and is often achieved by more invasive and inconvenient modes of administration such as continuous intravenous infusion. Transdermal drug delivery systems (TDDS), on the other hand, have the potential to achieve this sustained release which is useful for drugs with short biological half-lives without the inconvenience associated with intravenous infusion. However, not .all the drugs are suited for TDDS. Owing to good barrier function of skin mainly due to its lipophilic outermost layer, the stratum corneum, most drugs with hydrophilic structures permeate the skin too slowly to be of therapeutic benefit. This is reported to be due to hydrogen-bonding functionality on the permeant which drastically retard skin permeation. Cytarabine is known for its high hydrophilicity and plurality of polar functional groups capable of hydrogen bonding. Therefore, it becomes apparent that cytarabine would not easily permeate the skin. The disadvantages of TDDS include skin irritation, which is one of the possible side effects. Prodrug approach could be used to circumvent these setbacks. This approach has been investigated to enhance dermal and transdermal penetration of drugs with unfavourable intrinsic properties and it showed promising outcomes. Increased skin penetration of the drug could be achieved if delivered via its derivative with better physicochemical properties for transdermal penetration. The aims of this study were to determine the transdermal penetration of cytarabine and its synthesized amide, ester and carbamate derivatives and to establish a correlation, if any, between transdermal penetration and selected physicochemical properties. The alkylamide (5 compounds), alkylester (6 compounds) and carbamate (6 Compounds) derivatives of cytarabine were synthesized by standard chemical procedures, their structures confirmed by NMR and MS and they were evaluated for transdermal penetration using human epidermis as a model. The transdermal flux values of these derivatives were determined in vitro using Franz diffusion cell methodology. Quantification of compounds was achieved by using HPLC. Selected physicochemical properties (aqueous and lipid solubility; melting point and log D) of cytarabine derivatives were determined and assessed for any correlation with transdermal parameters of these compounds. The sleady-state flux value of cytarabine was found to be 3.7 In the N4-methoxypoly(ethylene glycol) homologous series, the first member, N4-methoxyethanolcytarabine carbamate, with a log D value of -1.20 exhibited the highest flux. In this series, no significant increase in transdermal delivery of cytarabine by its derivatives was observed. Moreover, no clear relationship between lipid and aqueous solubility, molecular weight and transdermal flux values was observed. In the alkylester and alkylamide homologous series, octanol solubility values increased whereas aqueous solubility decreased as the alkyl chain lengthened. As a consequence, the log 0 increases as the chain lengthens. Generally, the flux values of cytarabine and its derivatives are very low compared to those of compounds that are clinically administered by transdermal delivery system such as nicotine and scopolamine. Statistically significant skin penetration enhancement of cytarabine was achieved by N4-hexanoylcytarabine and cytarabine-5'-butanoate with log 0 values of 0.91 and -0.26 respectively. These compounds exhibited the highest flux values in their respective series. In comparison to the other members of their homologous series, they showed relatively good balance between lipid and aqueous solubilities. These findings highlight the importance of biphasic properties of compounds in optimisation of their skin penetration.
dc.publisherNorth-West University
dc.titleSynthesis and transdermal penetration of cytarabine and selected amide, ester and carbamate derivativesen

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    This collection contains the original digitized versions of research conducted at the North-West University (Potchefstroom Campus)

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