Pharmacokinetic studies of fluphenazine and four ester prodrugs
The purpose of present thesis work was to investigate the pharmacokinetics of FLU and four aliphatic esters, FLU-A, FLU-B, FLU-E and FLU-D, and in particular, the impact of the ester groups on the pharmacokinetics of the parent compound FLU after administration of the prodrugs in oil based injections. It was determined that the sesame oil/buffer partition coefficients (PC) decreased as the homogenous series of the ester chain length was increased, the effect of the chain length of the prodrug on the release rate of the corresponding prodrug from the oily depot. Furthermore, the results from 'in vitro ' enzymatic experiments using plasma, liver and muscle homogenates obtained from dog or human showed that lipophilicity of the esters predominated over other parameters such as enzymatic hydrolysis in determining the sustained production of FLU when the prodrugs were given as oil based intramuscular depot formulations. The roles of depot injection sites and proximal lymph nodes in the absorption kinetics of FLUand prodrug were investigated by intramuscular administration of either FLU base or FLU-D in sesame oil to groups of rats. The quantitative data suggested the involvement of the lymphatic system in the presystemic absorption of FLU and FLU-D after intramuscular administration of FLU-D in sesame oil. Finally, intravenous or intramuscular pharmacokinetics of FLU and four esters were investigated in dogs. The results showed that the chain length affected the kinetics of both FLU and the ester prodrugs. A pharmacokinetic model (s) was developed to simulate the disposition of FLU-D and the formation of FLU after either intravenous or intramuscular administration of FLU-D. Satisfactory fits of the simulated profiles with the observed data implies that the prolonged elimination profiles of FLU observed after intravenous administration could be rate limited by the ester chain length dependent distribution or redistribution of the prodrug from poorly perfused (fatty) deep compartments and subsequent hydrolysis in more highly perfused tissues while the ultimate rate limiting step in the absorption kinetics of FLU and prodrug after intramuscular administration could be the slow partitioning out of prodrug from the oily deposits at the injection sites and surrounding tissues such as proximal lymph nodes with the subsequent hydrolysis of the ester group in the body.
medicine, pharmacy, drugs, metabolism, antipsychotic agents
Doctor of Philosophy (Ph.D.)