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Prediction of Human Systemic, Biologically Relevant Pharmacokinetic Properties Based on Physicochemical Properties of Calcium Channel Blockers

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Prediction of Human Systemic, Biologically Relevant Pharmacokinetic Properties Based on Physicochemical Properties of Calcium Channel Blockers Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2012 PREDICTION OF HUMAN SYSTEMIC, BIOLOGICALLY RELEVANT PHARMACOKINETIC PROPERTIES BASED ON PHYSICOCHEMICAL PROPERTIES OF CALCIUM CHANNEL BLOCKERS Tafif Abdullah Al Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Pharmacy and Pharmaceutical Sciences Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/2868 This Thesis is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. © Abdullah Al Tafif, 2012 All Rights Reserved i PREDICTION OF HUMAN SYSTEMIC, BIOLOGICALLY RELEVANT PHARMACOKINETIC PROPERTIES BASED ON PHYSICOCHEMICAL PROPERTIES OF CALCIUM CHANNEL BLOCKERS A thesis submitted in partial fulfillment of the requirements for the degree of Master of Sciences at Virginia Commonwealth University. By ABDULLAH IBRAHIM ALTAFIF B.Pharm., Saudi Arabia, King Saud University, College of Pharmacy, 2001 Director: JÜRGEN VENITZ, M.D., PH.D. PROFESSOR, DEPARTMENT OF PHARMACEUTICS ii Acknowledgements I would like to give special thanks to my advisor Dr. Jürgen Venitz for all of his time, guidance, and endless support throughout this project. Without his backing, guidance, and broad knowledge, this task would not have been possible. Dr. Venitz, I have learned so many things from you during the past three years, which I will remember for all of my life. I would also like to thank my committee members Dr. Gerk, and Dr. Slattum, for their valuable time, constant support, and encouragement. Completion of this project would not have happened without your directions and help. I would also like to thank all of my colleagues and loved ones for putting up with me during the past three years, especially Gopichand and Apurvasena for their amazing friendship and help. A million thanks to my parents, who prayed for me to reach this achievement and succeed in my life. Finally, I would like to thank my wife for the great support and help during my study, who gave me the inner strength. Her support through the years has been an essential contribution to my completing the task of this work. iii Table of Contents Acknowledgements ................................................................................................................ iii List of Tables .......................................................................................................................... vi List of Figures ........................................................................................................................ vii List of Abbreviations .............................................................................................................. ix Abstract .................................................................................................................................... 1 Chapters 1 Introduction .................................................................................................................................... 4 1.1.1 Background ........................................................................................................................ 4 1.1.2 History of calcium channel blockers (CCB)...................................................................... 5 1.1.3 Chemical structures of CCB .............................................................................................. 7 1.1.4 Quantitative-structure pharmacokinetic relationships (OSPKR) .................................... 12 1.1.5 Pharmacokinetics (PK) of CCB ....................................................................................... 16 1.1.6 Pharmacodynamics (PD) of CCB .................................................................................... 17 2 Research Hypothesis .................................................................................................................... 19 2.1.1 Specific Aims .................................................................................................................. 19 3 METHODS ................................................................................................................................... 20 3.1.1 Definition of Biologically Relevant PK Variables .......................................................... 20 3.1.2 Definition of physiochemical (PC) Variables ................................................................. 22 3.2 Data Collection ..................................................................................................................... 24 3.2.1 Collection of PK variables ............................................................................................... 24 3.2.2 Collection of PC variables ............................................................................................... 28 3.3 Data Analysis ........................................................................................................................ 28 iv 3.3.1 Statistical distribution and collinearies ............................................................................ 28 3.3.2 Correlation analysis-PC variables ................................................................................... 28 3.3.3 Correlation analysis-PK variables ................................................................................... 29 3.3.4 Univariate relationships between PK and PC variabels .................................................. 29 4 RESULTS AND DISCUSSION .................................................................................................. 30 4.1.1 Comparison of PC properties .......................................................................................... 30 4.1.2 Comparison of PK properties .......................................................................................... 38 4.1.3 QSPKR ............................................................................................................................ 50 4.1.4 Overall conclusions ......................................................................................................... 61 Appendix I PK Summary of PK varianbles across studies (final values including number of studies) for CLtot and Vdss…………..….…......……………………………………………......…... 67 Appendix II (Summary of Human PK studies)…….....….………………….............……………...82 References ………………………………………………………………………………………103 v List of Tables Table 3.1. Estimation of in-vivo PK variables .................................................................................... 22 Table 3.2. PK classification of CCB .................................................................................................. 27 Table 3.3 Comparison of the therapeutic doses and the PK studies doses for different CCB.. ........ ..27 Table 4.1 Summary of physicochemical properties of CCB .......................................................... …34 Table 4.2 Statistical interpretations of CCB of PC variables correlation matrices ............................. 37 Table 4.3 Summary of the PK variables of CCB ................................................................................ 42 Table 4.4 Statistical interpretation of CCB PK variables correlation atrices…………………...…..42 Table 4.5 Comparison between CLint from smith et al and the current study ……....…………..….47 Table 4.6 Regressions between PC and PK Variables (all CCB) ...................................................... 62 Table 4.7 Regressions between PC and PK Variables without Amlodipine ..................................... 64 Table 4.8 Comparison between CCB and other drug classes as a function of logD7.4 ...................... 66 vi List of Figures Figure 1.1 General structure of 1,4 dihydropyridine .................................................................. 7 Figure 1.2 Chemical structures of CCB. ..................................................................................... 9 Figure 4.1 Distribution of MW ................................................................................................ 32 Figure 4.2 Distribution of nRot ................................................................................................ 32 Figure 4.3 Distribution of HBA ................................................................................................ 32 Figure 4.4 Distribution of HBD ................................................................................................ 32 Figure 4.5 Distribution of logP ................................................................................................. 33 Figure 4.6 Distribution of molar volume .................................................................................. 33 Figure 4.7 Distribution of logD7.4 ............................................................................................. 33 Figure 4.8 Distribution of PSA ................................................................................................. 33 Figure 4.8 (B) Correlation matrices of PC variables ......................................................................36 Figure 4.9 Distribution of CLtot ............................................................................................... 40 Figure 4.10 Distribution of Vdss ...............................................................................................
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