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Physiological Scaling Factors and Mechanistic Models for Prediction of Renal Clearance from in Vitro Data

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Physiological Scaling Factors and Mechanistic Models for Prediction of Renal Clearance from in Vitro Data PHYSIOLOGICAL SCALING FACTORS AND MECHANISTIC MODELS FOR PREDICTION OF RENAL CLEARANCE FROM IN VITRO DATA A thesis submitted to the University of Manchester for the degree of Doctor of Philosophy in the Faculty of Medical and Human Sciences 2016 DANIEL SCOTCHER Manchester School of Pharmacy Contents Contents ........................................................................................................................................... 2 List of Figures .................................................................................................................................. 6 List of Tables .................................................................................................................................... 9 Abstract .......................................................................................................................................... 11 Declaration ..................................................................................................................................... 12 Copyright statement ...................................................................................................................... 12 Abbreviations ................................................................................................................................. 13 Acknowledgements ....................................................................................................................... 16 Chapter 1. Key to opening kidney for in vitro-in vivo extrapolation entrance: The existing holes that prevent prediction of human renal drug disposition in health and disease! ........ 17 1.1 Introduction ........................................................................................................................... 17 1.2 Defining the need for more quantitative models ................................................................... 19 1.3 Getting a handle on renal drug elimination: Use of in vitro systems .................................... 22 1.3.1 In vitro systems for studying renal drug metabolism ........................................................ 22 1.3.2 Measurement of renal passive tubular permeability in vitro ............................................. 23 1.3.3 In vitro systems to study active transport in kidney.......................................................... 23 1.3.4 Mechanistic modelling of in vitro transporter kinetic data ................................................ 27 1.4 Understanding the physiology of kidney: The key system data in PBPK models ................ 28 1.4.1 Kidney weight, volume and blood flow ............................................................................. 28 1.4.2 Tubular flow rates and pH regulation ............................................................................... 31 1.4.3 Nephron number .............................................................................................................. 33 1.4.4 Tubule dimensions and surface area ............................................................................... 33 1.4.5 Proximal tubule cell number ............................................................................................. 36 1.4.6 Microsomal and cytosolic protein content of kidney......................................................... 36 1.4.7 Amount of specific drug metabolising enzymes in kidney ............................................... 39 1.4.8 Amount of specific drug transporters in kidney ................................................................ 39 1.5 Use of models for studying pharmacokinetics in kidney: Current status and IVIVE opportunities .................................................................................................................................. 40 1.5.1 IVIVE and models of renal drug metabolism .................................................................... 40 1.5.2 IVIVE and modelling of tubular excretion of drugs ........................................................... 42 1.5.3 Prediction of renal drug-drug interactions within PBPK paradigm ................................... 43 1.5.4 Assessing dosage adjustment in chronic kidney disease ................................................ 46 1.6 Perspective on current efforts ............................................................................................... 46 1.7 Conclusion ............................................................................................................................ 48 1.8 Aims of project ...................................................................................................................... 49 Chapter 2. Measurement of microsomal and cytosolic protein kidney and in vitro-in vivo extrapolation of renal metabolic clearance ................................................................................ 51 2.1 Introduction ........................................................................................................................... 51 2.1.1 Aims ................................................................................................................................. 52 2.2 Methods ................................................................................................................................ 53 2.2.1 Isolation of microsomal protein from dog kidney .............................................................. 53 2.2.2 Isolation of microsomal and cytosolic protein from human and rat kidney ...................... 55 2.2.3 Estimation of microsomal and cytosolic protein contents of tissues ................................ 57 2.2.4 Prediction of mycophenolic acid glucuronidation clearance in vivo ................................. 60 2.2.5 Data Analysis ................................................................................................................... 60 2.3 Results .................................................................................................................................. 61 2 2.3.1 Characterisation and optimisation of protein marker assays ........................................... 61 2.3.2 Estimation of microsomal protein content in dog kidney cortex and liver and comparison with intestine .............................................................................................................................. 64 2.3.3 Estimation of MPPGK and CPPGK in human kidney cortex ........................................... 69 2.3.4 In vitro glucuronidation of mycophenolic acid by human kidney microsomes and IVIVE scaling ....................................................................................................................................... 71 2.4 Discussion............................................................................................................................. 76 2.4.1 Suitability of microsomal and cytosol protein markers for correction of protein losses ... 77 2.4.2 Species and tissue differences in subcellular protein content estimates ......................... 79 2.4.3 Impact on updated MPPGK scaling factors on renal metabolic clearance predictions ... 80 2.4.4 Conclusion ........................................................................................................................ 81 Chapter 3. Development of novel methodology for measurement of proximal tubule cell number in human kidney .............................................................................................................. 82 3.1 Background ........................................................................................................................... 82 3.1.1 Aims ................................................................................................................................. 83 3.2 Methods ................................................................................................................................ 84 3.2.1 Reagents .......................................................................................................................... 84 3.2.2 Source of human and pig kidney ..................................................................................... 84 3.2.3 Sampling and embedding of pig kidney ........................................................................... 84 3.2.4 Microtome sectioning and mounting ................................................................................ 84 3.2.5 Deparaffinising and rehydration ....................................................................................... 84 3.2.6 Periodic acid Schiff – Orange G stain .............................................................................. 85 3.2.7 Immunohistochemistry ..................................................................................................... 85 3.2.8 Dehydration, mounting and scanning of slides ................................................................ 86 3.3 Results .................................................................................................................................. 87 3.3.1 Stereological processing of kidney .................................................................................. 87 3.3.2 Staining and immunohistochemistry ................................................................................ 88 3.4 Discussion............................................................................................................................. 94 3.4.1 Identification of
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