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Thesis (M.Sc.). / Written for the Dept. of Mathematics and Statistics. Title from title page of PDF (viewed 2008/01/16). Includes bibliographical references.

Effects of age, dosage regimen, dose level, and routes of administration on the pharmacokinetics of acrylamide (ACR) and theophylline (TP) in Fischer 344 rats have been studied. ACR treatment consisted of administration of a single subtoxic dose or of multiple doses known to induce neurotoxicity to 5 and 11 week old rats. The effects of age and dosing regimen on the determination of pharmacokinetic parameters were studied. Multiply dosed rats had significantly longer plasma half lives than the singly dosed animals. Clearance values in the plasma were also significantly decreased following multiple dosing. Animals treated with TP received a single dose at different dose levels either intravenously or orally. No statistical difference was found between beta, Vbeta , and Cl based on dose level. All pharmacokinetic parameters were similar in magnitude to literature values for humans. Following oral dosing, plasma levels of TP were constant for the duration of the experiment. (Abstract shortened with permission of author.)

Purpose: To develop an agent-based, discrete-event, synthetic model that integrates the existing knowledge about intestinal absorption and disposition of baicalein (Ba) and dynamically represents the pharmacokinetic properties of Ba. To validate the model by matching simulated observations to bi-directional Caco-2 transport profiles of Ba. / Methods: A 3D multi-agent system extending the previous 2D in silico analogue of Caco-2 cell monolayer was used to study the pharmacokinetic properties of Ba. The model specification was based on previous study findings. Our model consisted of three 3D spaces and two 2D membranes: apical space (S1), intracellular space (S2), basolateral space (S3), apical membrane (M1), and basolateral membrane (M2). Validated enzyme components (UGTs and SULTs) and binder components (BINDERs) were placed in S2. Validated efflux transporter components (BCRPs, MRP2s, MRP1s and MRP3s) were placed at M1 and M2 respectively. Initially, Solutes (BA) were loaded to either S1 or S3. From there, they penetrated into S2 according to a validated, passive transport algorithm. Within S2, BA could be transformed into Baicalein-Glucuronide (BG) by UGTs or to Baicalein-O-Sulfate (BS) by SULTs. These metabolites were pumped out to either S1 or S3 by the active transport of BCRPs, MRP2s, MRP1s and MRP3s. Simulated results were then compared to corresponding wet-lab data to assess similarity based on the pre-specified similarity criteria. An iterative refinement protocol combined with Monte-Carlo simulation was employed to parameterize the model. Finally, the in silico parameters had also been mapped to the classical pharmacokinetic parameters. / Results: The simulated results captured the preset qualitative and quantitative features of the wet-lab observations. The feasible parameter set showed that substrate inhibition happened in both conjugation pathway of Ba. The simulation results suggested that sulfation pathway was dominated at low concentrations and that SULT was more inclined to substrate inhibition than UGT. All these findings were consistent with the previous outcomes from a catenary model. In addition, a micro-hypothesis that BS’s apical efflux transporter could be inhibited by Ba at high loading concentration was implemented to address the changing preference of the distribution of BS. / Conclusion: The mechanisms represented by our model are plausible. Our novel modeling approach could dynamically represent the pharmacokinetics of bi-directional transport of Ba in Caco-2 system. Furthermore, through the model development, we suspect there is inhibition of BS’s apical efflux transporter at high loading concentration of Ba, which is worthy of further investigation. / 研究目的：建立一個基於離散事件，並由智慧單元體組成的組合模型。該模型將整合與黃芩素小腸吸收和處置相關的已有知識，從而動態呈現黃芩素的藥動學性質。黃芩素在Caco-2系統中進行的雙向轉運實驗資料將被用來對該模型進行校驗。 / 研究方法：一個新的三維多智慧體系拓展自已有的二維Caco-2單層細胞體系模型，將被用來研究黃芩素的藥動學特徵。模型的配置將基於已有的研究發現。該模型由三個三維的空間對象和兩個二維的膜對象組成，他們是：頂端空間（S1）,細胞內空間（S2）,基底空間（S3）,頂端膜（M1）,和基底膜（M2）。已校驗的酶物件（UGTs和SULTs）和結合蛋白物件（BINDERs）將被設置在空間物件S2內。已校驗的外排轉運體對象（BCRPs, MRP2s, MRP1s和MRP3s）將被分別設置在膜物件M1和M2上。起始階段，黃芩素物件(BA)將被載入到空間物件S1或S3中。從載入空間出發，BA將基於已校驗的被動轉運演算法進入細胞內空間S2。在S2內，BA將通過UDP-葡萄糖醛酸轉移酶對象（UGTs）被轉化為黃芩苷對象（BG），或是通過硫酸轉移酶對象（SULTs）轉化為硫酸黃芩素物件（BS）。這些代謝產物物件將通過乳腺癌耐藥蛋白物件（BCRPs）和多種多藥耐藥相關蛋白物件（MRP2s, MRP1s和MRP3s）主動泵出到空間S1或S3中。模擬結果將按照預先設定的相似性判斷標準與對應的實驗資料進行比對。我們將通過結合蒙特卡洛模擬的迴圈反覆運算優化方案進行模型的參數化。最終，該模型參數將與傳統的藥動學模型參數建立起相關映射關係。 / 研究結果：模擬結果能夠很好刻畫實驗觀察到的定性和定量特徵。可行的參數集顯示底物抑制效應在黃芩素的兩條代謝通路都有發生。模擬結果顯示在低濃度下硫酸化通路是主要代謝途徑，且硫酸轉移酶相較於UDP-葡萄糖醛酸轉移酶更易被底物抑制。所有這些發現都與之前鏈式模型得到的結論相吻合。此外，一個關於硫酸黃芩素的頂端外排轉運體能夠被高濃度黃芩素抑制的微假設被引入到模型中來解釋硫酸黃芩素分佈偏好的變化。 / 結論：模型所呈現的機制是可行的。我們新穎的模型化方法能夠動態地呈現黃芩素在Caco-2系統中雙向轉運的藥動學特徵。此外，通過模型，我們推測硫酸黃芩素的頂端外排轉運體可能存在被高濃度黃芩素抑制的現象，這值得進一步的深入研究。 / Zhu, Xiao. / Thesis M.Phil. Chinese University of Hong Kong 2015. / Includes bibliographical references (leaves 115-123). / Abstracts also in Chinese. / Title from PDF title page (viewed on 12, October, 2016). / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only.

by Walubo Andrew. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1991. / Bibliography: leaves 148-174. / ABSTRACT --- p.i / declaration --- p.iv / acknowledgements --- p.v / Chapter chapter 1 --- general introduction --- p.1 / Chapter chapter 2 --- literature review --- p.5 / Chapter section 1 --- isoniazid --- p.5 / Chapter section 2 --- rifampicin --- p.19 / Chapter section 3 --- pyrazinamide --- p.27 / Chapter section 4 --- an overview of the use of antituberculous drugs in uganda and hong kong --- p.30 / Chapter section 5 --- review of analytical methods --- p.40 / Chapter section 6 --- conclusions from the reviews --- p.44 / Chapter chapter 3 --- some principles of pharmacokinetics --- p.47 / Chapter section 1 --- introduction --- p.47 / Chapter section 2 --- application of pharmacokinetics --- p.55 / Chapter chapter 4. --- aims of the present project --- p.66 / Chapter chapter 5 --- chromatographic methods --- p.68 / Chapter section 1 --- a simultaneous assay for isoniazid and hydrazine metabolite in plasma and cerebrospinal fluid in the rabbit --- p.68 / Chapter section 2 --- a simultaneous assay for rifampicin and pyrazinamide in human plasma --- p.89 / Chapter chapter 6 --- the pharmacokinetics of isoniazid and hydrazine metabolite in the plasma and cerebrospinal fluid of rabbits --- p.91 / Chapter chapter 7 --- the disposition of anti-tuberculous drugs in the plasma of elderly patients --- p.108 / Chapter SECTION 1 --- METHODS --- p.109 / Chapter SECTION 2 --- CLINICAL ASSESSMENT --- p.112 / Chapter SECTION 3 --- GENERAL FINDINGS. --- p.117 / Chapter 1)- --- THE DISPOSITION OF ISONIAZID AND HYDRAZINE METABOLITE IN THE PLASMA OF ELDERLY PATIENTS --- p.117 / Chapter 2) - --- "THE DISPOSITION OF ISONIAZID, PYRAZINAMIDE AND RIFAMPICIN IN THE PLASMA OF ELDERLY PATIENTS" --- p.129 / Chapter SECTION 4 --- CASE REPORT --- p.139 / Chapter CHAPTER 8 --- p.145 / Chapter SECTION 1 --- GENERAL CONCLUSIONS --- p.145 / Chapter SECTION 2 --- FUTURE STUDIES --- p.147 / REFERENCES --- p.148 / APPENDICES: --- p.AO / Chapter APPENDIX A --- (WORK SHEETS) --- p.AO / Chapter APPENDIX B --- (SCIENTIFIC COMMUNICATIONS) --- p.BO

Bibliography: leaves 168-188. Investigates whether systematic absorption and peak plasma concentration of infiltrated doses of the local anaesthetic agent lignocaine are directly related to the regional blood flow of the injection site.

Thesis (M.S.P.H.)--University of Michigan, 1937.

Thesis (M.S.)--University of Michigan, 1934.

Thesis (M.S.)--University of Michigan, 1935. / Also issued in print.

Thesis (M.S.)--University of Michigan, 1934.