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Clearance Concepts Ln the Kidney CLEARANCE CONCEPTS LN THE KIDNEY Gina Louise Sirianni A thesis submitted in confonnity with the requirements for the degree of Master of Science Graduate Department of Pharmacology, University of Toronto O Copyright by Gina Louise Sirianni ( 1997) National Library Bibliothêque nationale l*l of Canada du Canada Acquisitions and Acquisitions et Bibliographie Services services bibliographiques 395 Wellington Street 395. rue Wellington OttawaON KIA ON4 Ottawa ON KIA ON4 Canada Canada The author has granted a non- L'auteur a accordé une licence non exclusive licence allowing the exclusive permettant à la National Library of Canada to Bibliothèque nationale du Canada de reproduce, loan, distribute or seIl reproduire, prêter, distribuer ou copies of this thesis in microform, vendre des copies de cette thèse sous paper or electronic formats. la forme de microfiche/film, de reproduction sur papier ou sur format électronique. The author retains ownership of the L'auteur conserve la propriété du copyright in this thesis. Neither the droit d'auteur qui protège cette thèse. thesis nor substantial extracts fiom it Ni la thèse ni des extraits substantiels may be printed or othenvise de celle-ci ne doivent être imprimés reproduced without the author's ou autrement reproduits sans son permission. autorisation. To My Parents Clearance Concepts in the Kidney Gina Louise Sirianni (M.Sc.), 1997 Department of Pharmacology, University of Toronto (Abstract) The kidney is an important elirninating organ. capable of metabolism and excretion. The fractional excretion value (FE, unbound urinary clearance normalized to glomemlar filtration rate) is typically used to detemine whether a compound is net fdtered (FE = I). reabsorbed (FE < 1) or secreted (FE > 1) by the kidney. It was hypothesized that competing routes of elimination within the kidney wiU influence the clearance eshate of each other. The hypothesis was first tested with cornputer simulations based on a physiological model of the kidney and parameters describing the rend handling of enalapril, an angiotensin converting enzyme inhibitor that is both rnetabolized and excreted unchanged by the kidney. Since the location of endapril metabolism was unknown. simulations were based on two possible models, one which incorporated intracellular metabolism of enalapril, and another which incorporated intraiuminal metabolism of enalapril. Results of the simulation study showed that the excretory clearance estimate was decreased in the presence of luminal or cellular metabolisrn while metabolic clearance was affected differentialiy. depending upon the site of rend metabolism. The renal metabolic clearance was predicted to decrease with excretion for the intracellular model, but would increase for the intraluminal model. Studies were then performed in the nonfiltenng isolated perfused rat kidney to determine the site of rend enalapril metaboiism with data obtained for enalapril and its metabolite. enalaprilat. The observations closely matched the predictions for intracellular metabolism. A final set of studies with enalapril and an esterase inhibitor. paraoxon, was performed in the renal S9 fraction and in the isoiated perfused rat kidney preparation. The results demonstrated that unnary clearance estimates were indeed reduced by the presence of inmenal metabclism. Since the urinary clearance estimate was affected by intrarenal metabolisrn, FE was not an accurate indicator for the net flux of dmg through the kidney. I greatly appreciate the Mie and guidance that my supervisor, Dr. K. Sandy Pang has provided throughout the course of my studies. Through her suggestions, comments. and criticisrns. Dr. Pang has seengthened rny scientific capabilities and my ability to think cntically. 1 would also like to thank my advisor, Dr. Lado Endrenyi. for his advice and encouragement. Although the membea of the lab have changed over the past two years. the group has always consisted of intelligent and amicable people. who have been a pleasure to work with. Thank you all for making my stay here an enjoyable and memorable experience. 1 would especially like to thank my "helpers" for kidney surgery, Dr. Wanping Geng. Dr. Margaret Doherty and Mr. Ford Barker. 1 also thank my boyfnend, Armenio Martins, for his encouragement and thoughtfulness. Lastly. but most irnportantly, I thank my mother. father, and brother, Joe for their continuous love. support and encouragement. Financial support from the University of Toronto Open Fellowship offered by the School of Graduate Studies was appreciated. 3.3 THEORETICAL ................................................................................................................. 26 3.4 METHODS ........................................................................................................................... 28 3.5 RESULTS .............................................................................................................................. 31 3.5.1 Kidney as the ody elirninating organ .............................................................................. 31 3.5.2 Simulations on rend disposition of enalapril .................................................................. 31 3.6 DISCUSSION ............... ,. ................................................................................................... 36 3.7 STATEMENT OF SIGNIFICANCE OF CHAPTER 3 ..................................................... 39 CHAPTER 4: INTRACELLULAR AND NOT INTkUUMIbJAL ESTEROLYSIS OF ENALAPRIL IN KIDNEY: .......................................................................................................... -10 4.1 ABSTRACT .................,., .................................................................................................... 41 4.2 INTRODUCTION ...............................................................................................................-42 4.3 MATERIALS AND METHODS ..................................................................................... 43 Source of materiais .......................................................................................................... 43 Kidney Perfusion ............................................................................................................ 44 Viability of the PK......................................................................................................... 16 Protein Binding ..............................................................................................................46 Andytical procedures ......................................................................................................47 Calculations..................................................................................................................... 47 Simulations ....................................................................................................................49 Statistics ..........................................................................................................................53 4.4 RESULTS ..............................................................................................................................54 4.4.1 Viability of the Perfused Rat Kidney Preparations .......................................................... 54 4.4.2 Protein Binding ...............................................................................................................55 4.4.3 The Non-Filtering Kidney............................................................................................... 55 4.4.4 Simulations .....................................................................................................................57 4.5 DISCUSSION ....................................................................................................................... 59 4.6 STATEMENT OF SIGNIFICANCE OF CHAPTER 4 ...................................................... 62 CHAPTER 5: INHIBITION OF ENALAPRIL ESTEROLYSIS BY PARAOXON IN THE ISOLATED PERFUSED RAT KIDNEY INCREASES URINARY CLEARANCE OF ENALAPRIL ................................................................................................................................ 63 5.2 INTRODUCTION ................................................................................................................ 65 5.3 MATERIALS AND METHODS .......................................................................................... 66 5.3.2 Rend S9 Fraction ............................................................................................................ 66 5.3.3 Partition Coefficient for Enaiapril at Various pH ......................................................... 67 5.3.1 Experiments in the Single-Pass Isolated Perfused Rat Kidney (IPK) ............................. 68 5.3.4.1 Viability Studies in the IPK with Paraoxon .............................................................. 69 5.3.4.2 Inhibition Experiments with [3~~~nalapnland Paraoxon in the IPK ....................... 69 5.3.5 Thin Layer Chromatographic Assay for Enalapril and Enalapnlat.................................. 71 5.3.6 Statistics .......................................................................................................................... 71 5.3.7 Calculations....... .... ...................................................................................................71 5.4 RESULTS .............................................................................................................................
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