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Oil and emulsion vehicles have been shown to alter the oral absorption of many drugs. This may be due to enhanced lymph flow and/or altered gastro-intestinal motility in the presence of the oils. The oral absorption of a model compound (DOT) in the presence of three chemically different oils, arachis oil, Miglyol 812 and liquid paraffin was investigated in rats, the influence of lymphatic absorption and gastro-intestinal motility being determined. The findings were applied to the for.mulation of the'steroid prednisolone, in an attempt to produce elevated more uniform plasma drug levels by enhancing lymphatic absorption. The rank order for total DOT absorption from 1m! Volumes of different vehicles was arachis oil > Miglyol 812= water containing 6% Tween 80 > liquid paraffin. The concentration of DDT in lymph collected via thoracic duct cannblae in anaesthetised rats was greatest in the presence of arachis oil, there being no difference between Miglyol 812 and liquid paraffin. Using a gamma camera the gastric emptying rate and total intestinal transit of 9~c-sulphur colloid, an oil phase marker, was shown to be faster in the presence of 1ml liquid paraffin than the other two oils. The oral absorption of 3H-prednisolone was independent of the nature of the oily vehicle (30pl volumes) and was not selectively absorbed into the lymph. Esterification to 3H-prednisolone-21-palmitate increased the lipophilicity of the drug but did not stimulate selective lymphatic absorption and reduced oral absorption following administration in arachis oil. Lymphatic absorption of the ester was not promoted by administration in 1ml arachis oil. Only the lymphatic absorption of compounds exhibiting selective uptake into the lymph may be enhanced by the presence of a suitable lipid vehicle. Altered gastro-intestinal motility in the presence of lipids may have greater potential for enhancing the absorption of a wider variety of compounds.

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This thesis attempts to determine the role of 5-hydroxytryptamine (5-HT) in rodent models of anxiety. Using the elevated X-maze it was possible to detect dose-dependent anxiolytic effects of diazepam and dose-dependent anxiogenic effects of FG 7142 (a β-carboline derivative) and idazoxan. The fear-potentiated acoustic startle paradigm also detected the effects of these compounds but the results were neither dose-dependent nor very reproducible. Using the X-maze the 5-HT1A receptor partial agonist ipsapirone had no effect after either acute or chronic treatment, while both the 5-HT2 receptor antagonist, ritanserin, and the 5-HT3 receptor antagonist, ondansetron, had anxiolytic activity after chronic treatment. Using in vivo mirodialysis it was demonstrated that extracellular levels of 5-HT in the ventral hippocampus increase when the animal is on the X-maze, and both diazepam and F 2692 (1-(3'-trifluoro-methylphenyl) 1.4- dihydro 3-amino 4-oxo 6-methyl pyrldazine) reduced the increased 5-HT levels and produced an anxiolytic behavioural profile in the same animal. Thus the inhibition of increased 5-HT release may be important for anxiolytic activity. However, ipsapirone also reduced the increased 5-HT but did not produce an anxiolytic profile. The lack of an anxiolytic effect may be the result of postsynaptic 5-HT1A receptor stimulation. Rats reared in isolation immediately post-weaning (21 days of age) displayed enhanced locomotor activity and an anxiogenic profile on the X-maze. This anxiogenic profile was neither reversed by resocialisation of the isolation-reared rats nor produced by isolation of adult socially housed animals, indicating a permanent developmental change. Isolation-reared rats had reduced stimulated release of 5-HT measured in the frontal cortex, indicating reduced presynaptic function and enhanced responsiveness to agonists acting at postsynaptic 5-HT1A and 5-HT2 receptors, suggesting supersensitivity at these sites. Overall, 5-HT appears to be involved in anxiety with 'anxious' behaviour either on the X-maze or by isolation-rearing causing changes in 5-HT function. Thus one of the mechanisms of action of established and putative anxiolytic and anxiogenic compounds may be via modulation of the ascending dorsal raphe serotonergic neuronal pathways. All work in this thesis was undertaken under Home Office Personal Licence PIL 70/02103 and Project Licences PPL 40/0380 (Nottingham University) and PPL 70/00349 (SmithKline Beecham).

The role of deoxyribonucleic acids in the cell has made DNA an attractive target for drug molecules. The anthracycline antitumour antibiotics are potent cytotoxic agents that have found widespread use in cancer chemotherapy. Nogalamycin binds DNA through intercalation, preferentially to 5'-TpG and 5'-CpG sites, by threading through the DNA helix and interacting with both the major and minor grooves simultaneously. In this thesis, the interaction of nogalamycin with the 5'-TpG site has been investigated using synthetic oligonucleotide duplexes and a combination of high-resolution NMR techniques and NOE-restrained molecular dynamics simulations. The solution structure of the 1: 1 complex with d(ATGCAT)2 is described with NOE data unambiguously identifying the position and orientation of the bound drug molecule, allowing conclusions to be drawn regarding the specificity for the TpG site. Binding at one TpG site sterically blocks the interaction at the symmetrically equivalent CpA site. The structural studies are extended to investigate by NMR the role of solvation in drug- DNA recognition and binding. Based on the sign and magnitude of solute-solvent NOEs, it is shown that only a small subset of water molecules visible in the crystal and MD structures are found to be bound in the solution complex, and that a number of these are involved in mediating drug-DNA interactions. The role of the dynamic network of water molecules in stabilising the complex in solution is discussed. Finally, the binding of nogalamycin at a TpG site carrying a DNA strand break has been investigated using a novel designed single-stranded intermolecular duplex consisting of two hairpins stabilised by GAA loops [d(ACGAAGTGCGAAGC)]. Although stacking of the two hairpins is weak, nogalamycin is shown to bind and stabilise a 1: 1 complex by binding at the intercalation site. The complex is discussed in terms of the mechanism by which nogalamycin is able to bind to premelted duplex DNA.