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Date of Award

2006

Document Type

Dissertation - Pacific Access Restricted

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Pharmaceutical and Chemical Sciences

First Advisor

James Uchizono

First Committee Member

Xiaoling Li

Second Committee Member

Paul Williams

Third Committee Member

James Blankenship

Fourth Committee Member

Sara Kenkare-Mitra

Abstract

Serotonin (5-hydroxytryptamine, 5-HT) has been heavily implicated in the pathophysiology of depression and although its changes in the brain has been well studied using microdialysis, the analysis of its time data is often insufficient as pharmacokinetic (PK) and pharmacodynamic (PD) concepts are often neglected. The works in this dissertation attempt to further explore 5-HT time data via mechanism-based PK/PD modeling. The first work explored the dorsal raphe nucleus (DRN) in which the desensitization of 5-HTIA autoreceptors has been implicated in the several-week delay in onset of therapeutic response to antidepressants. An extension of a standard indirect-response pharmacodynamic modeling approach was used to account for the stimulation of locally administered citalopram on the production of 5-HT in the DRN and the nucleus accumbens. The overall model reasonably captured the time courses of 5-HT in both regions of the brain and predicted 5-HT concentrations in the DRN under a different (subcutaneous) dosing scheme. This model is the first to quantitatively explore an important control mechanism of central 5-HT output as perturbed by an antidepressant administration. The second work explored the combination treatment of citalopram, a serotonin selective reuptake inhibitor (SSRI), and WAY-100635, a 5-HT 1A receptor antagonist. Citalopram plasma kinetics was designated as fixed functions driving the dynamics of 5-hydroxytryptamine (5-HT) output in rat ventral hippocampus assumed in a standard indirect-response PD model which was then extended to fit the PD data for the combination treatment to account for two drugs acting synergistically on separate processes to modulate the same PD endpoint. Contrary to previous conclusions drawn based on peak 5-HT level, simulations from this modeling work showed that the potentiation of WAY-100635 in terms of AUEC (area under the effect curve) is minimally significant. Mechanism based PK/PD modeling as a way to explore pharmacological mechanism is further demonstrated in the third work which explored the mechanism of cancer cell kill in the presence of P-glycoprotein induction. Results from this modeling work suggest the need for reducing therapy-induced P-glycoprotein induction via optimizing dosing schedules to achieve maximal cancer cell reduction.

Pages

200

ISBN

9780542557743 , 0542557746

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