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Fengfeifeiff2020phd.Pdf (4.044Mb) In vitro and in vivo studies on the binding and permeation of ketotifen and norketotifen atropisomers in the central nervous system Feifei Feng July 2019 2 Abstract Ketotifen (K) is a first-generation antihistamine with antiinflammatory potency. It penetrates the blood-brain barrier (BBB) and causes a sedative side effect. Norketotifen (N) is an active metabolite of K. The S-atropisomer of N (SN), however, has antihistaminic and antiinflammatory properties but less sedating side effect than RN and K. This may be due to: (1) higher concentrations of K and RN than SN in the central nervous system (CNS) and/or (2) higher affinity of K and RN than SN for rat brain H 1-receptors. The aim of this thesis was to investigate the mechanism of why SN lacks a sedative side effect. To determine concentrations of racemic K and N and atropisomers of K and N in buffer solutions and bio-matrices, nonchiral and chiral high-performance liquid chromatography (HPLC) assays were developed and validated. Log P and log D of K and N (both octanol/buffer and liposomes/buffer) were determined to aid in interpretation of in vitro cell studies. Rat brain endothelial (RBE4) and colorectal adenocarcinoma (Caco-2) cell monolayers were used as in vitro models of the BBB to study the stereoselective uptake and permeability of K and N atropisomers. To investigate the distribution of K and N atropisomers between brain tissue and plasma, the total and free brain-to-plasma (B/P) ratios of K and N atropisomers were measured 5 min post-administration of racemic K and N through the rat tail vein. The affinity of K and N atropisomers to brain H 1 receptors was investigated by determining the extent of inhibition of [ 3H] mepyramine binding to H 1 receptors in rat brain cell membranes. The in vitro studies indicated active mechanisms for transporting K and N in both RBE4 and Caco-2 cell lines; however, none of these mechanisms were stereoselective . Interestingly, for both cell lines, more N was found binding non- specifically to cell membranes than that of K, though in a non-stereoselective manner. Liposomes/buffer distribution studies aided in interpretation of these results. i Similarly, the total and free B/P ratios of K and N atropisomers suggested a predominant influx mechanism involved in transporting of K and N through the rat BBB. However, this mechanism was not stereoselective for either K or N atropisomers . In addition, K and N non-specifically bound to rat plasma protein and brain tissues in different degree but the non-specific binding was not stereoselective either. In contrast, H 1 receptor affinity results suggested a stereoselective binding of SN for the H1 receptors in rat brain, in that SN had a lowest affinity compared with RN, SK and RK. Significant differences in the affinity for the H1 receptors were found between SN and SK, SN and RK, moreover, between SN and RN . Although the difference was significant but not substantial compared to some published stereoselective affinity for the H1 receptors, a similar degree of difference was observed and published by other research groups. Thus the lowest affinity of SN for the H1 receptors could participate in the observed less sedative effect caused by SN. In conclusion, there was no stereoselective transport of SN through the BBB either in vitro or in vivo , and there was no stereoselective non-specific binding of SN to rat plasma proteins or brain tissues. The lower sedative effect of SN is due to a lower uptake of N than K into the brain and reduced binding of SN to CNS H 1- receptors . ii Acknowledgements I gratefully acknowledge School of Pharmacy, which give me the chance to be a PhD candidate and support me financially. I gratefully acknowledge my supervisors for their support. My primary supervisor, Professor Ian G. Tucker, and my secondary supervisor Associate Professor Paul Fawcett. They guided me through my research work, encouraging me to “think like a scientist” and helped me when I was struggling with my writing. Dr Hu Zhang, he was my third supervisor early in my research, though he has never stopped helping and supporting me in my study and life . I want to acknowledge Professor Pauline Norris and Dr Dorothy Saville, who have been kindly checking on me and taking care of me through my study. I wish to acknowledge my parents for loving me , and supporting me both financially and mentally. My mother and father, Lili Yin and Gaimin Feng, have been supporting me in all the ways they can in my study and my life. I wish to acknowledge all my friends for being there whenever I needed help. Dunedin, New Zealand, 2019 Feifei Feng iii Publication to date arising from this thesis Feng, F., Fawcett, J. P., Zhang, H. & Tucker, I. G. (2019) Cell based and H 1-receptor binding studies relative to the sedative effects of ketotifen and norketotifen atropisomers. J. Pharm. Pharmacol. (Accepted) Conference presentations arising from this thesis Feng, F., Zhang. H, Fawcett, J. P., Yang, L., Tucker, I. G. Stereoselectivity of ketotifen transport in rat brain endothelial cells. Annual meeting and exposition of American Association of Pharmaceutical Scientists (AAPS) , Washington DC, USA (23-27 October 2011) . Feng, F., Yang, L., Fawcett, J. P., Tucker, I. G. Ketotifen uptake by rat brain endothelial (RBE4) cells is stereoselective. Proceedings of the ASCEPT Christchurch, NZ Meeting (28-30 August 2011). Feng, F., Fawcett, J. P., Tucker, I. G., Uptake of atropisomers of ketotifen and norketotifen into REB4 cells. 15 th Annual Formulation and Delivery of Bioactives Conference , Dunedin, NZ (13-14 February 2013). Feng, F., Fawcett, J.P., Tucker, I. G. Unexpected in vitro cell uptake of norketotifen compared with ketotifen. Abstracts of the Annual Australasian Pharmaceutical Science Association (APSA) Conference, Dunedin, NZ (8-11 December 2013). iv Table of Contents CHAPTER 1 INTRODUCTION 1 1.1 H ISTAMINE , HISTAMINE RECEPTORS 1 1.2 H 1 RECEPTOR ANTAGONISTS 5 1.3 K ETOTIFEN AND NORKETOTIFEN 9 1.4 C HIRALITY 13 1.4.1 C ONCEPTS 13 1.4.2 C HIRALITY IN BIOLOGICAL SYSTEMS 14 1.4.3 C HIRALITY IN ABSORPTION , DISTRIBUTION , METABOLISM AND ELIMINATION 15 1.5 T HE BBB AND ITS CHARACTERISTICS 17 1.5.1 W HAT IS THE BBB? 17 1.5.2 T HE BBB FUNCTION 20 1.5.3 G ENERAL RULES FOR PASSAGE THROUGH THE BBB 22 1.6 T RANSPORTERS AT THE BBB 22 1.6.1 E FFLUX TRANSPORTERS 23 1.6.2 O THER TRANSPORTERS (INFLUX TRANSPORTERS ) 26 1.7 S TEREOSELECTIVE TRANSPORTERS AND RECEPTORS AT THE BBB 31 1.8 A IM OF THIS THESIS 32 CHAPTER 2 NONCHIRAL HPLC ASSAY DEVELOPMENT AND VALIDATION 34 2.1 I NTRODUCTION 34 2.2 M ATERIALS 34 2.2.1 C HEMICALS AND REAGENTS 34 2.2.2 I NSTRUMENTATION (HPLC SYSTEM ) 35 2.3 A SSAY DEVELOPMENT AND VALIDATION 35 2.3.1 C HROMATAGRAPHY 35 2.3.2 S AMPLE PREPARATION 36 2.3.3 V ALIDATION 37 2.4 R ESULTS AND DISCUSSION 39 2.4.1 A SSAY DEVELOPMENT 39 2.4.2 A SSAY VALIDATION 41 CHAPTER 3 PARTITION AND DISTRIBUTION COEFFICIENTS OF KETOTIFEN AND NORKETOTIFEN 44 v 3.1 I NTRODUCTION 44 3.2 M ATERIALS 45 3.3 M ETHODS 45 3.3.1 A SSAY 45 3.3.2 L OG P OCTANOL /WATER : E FFECT OF TEMPERATURE 45 3.3.3 L OG D OCTANOL /BUFFER : E FFECT OF TEMPERATURE 46 3.3.4 L OG D LIPOSOME /BUFFER 46 3.3.5 S TATISTIC ANALYSIS 47 3.4 R ESULTS 48 3.4.1 L OG P OCTANOL /WATER : E FFECT OF TEMPERATURE 48 3.4.2 L OG D OCTANOL /BUFFER : E FFECT OF TEMPERATURE 49 3.4.3 L OG D LIPOSOME /BUFFER 51 3.5 D ISCUSSION 52 CHAPTER 4 CHIRAL HPLC ASSAY DEVELOPMENT AND VALIDATION 53 4.1 I NTRODUCTION 53 4.2 M ATERIALS 54 4.3 A SSAY DEVELOPMENT 54 4.3.1 M ETHODS OF ASSAY DEVELOPMENT 54 4.3.2 R ESULTS AND DISCUSSIONOF ASSAY DEVELOPMENT 59 4.4 A SSAY VALIDATION 63 4.4.1 M ETHODS OF ASSAY VALIDAITON 63 4.4.2 R ESULTS AND DISCUSSION OF ASSAY VALIDATION 64 4.5 A TROPISOMERIC PURITY OF SINGLE ATROPISOMERS 74 4.5.1 M ETHODS 74 4.5.2 R ESULTS AND DISCUSSIONS 75 CHAPTER 5 UPTAKE AND PERMEATION STUDIES OF KETOTIFEN AND NORKETOTIFEN IN CELL MODELS OF THE BBB 79 5.1 I NTRODUCTION 79 5.2 M ATERIALS 80 5.3 M ETHODS 81 5.3.1 S TUDIES IN RBE4 CELLS 81 5.3.2 S TUDIES IN CACO -2 CELLS 87 5.4 R ESULTS 90 5.4.1 B INDING OF K AND N ATROPISOMERS TO RBE4 CELL MEMBRANES 90 vi 5.4.2 C YTOTOXICITY OF K AND N TO RBE4 CELL MONOLAYERS 91 5.4.3 INITIAL UPTAKE EXPERIMENTS 92 5.4.4 P ERMEABILITY OF CACO -2 CELL MONOLAYERS (LOADING RACEMATES ) 99 5.5 D ISCUSSION 102 5.5.1 E FFECT OF ATP DEPLETION 102 5.5.2 U PTAKE AND ASSOCIATION 102 5.5.3 E FFECT OF TEMPERATURE ON RBE4 CELL UPTAKE 102 5.5.4 RBE4 UPTAKE AND CACO -2 MONOLAYER PERMEABILITY STUDIES 103 CHAPTER 6 IN VITRO STUDIES OF THE BINDING OF KETOTIFEN AND NORKETOTIFEN ATROPISOMERS TO CNS H 1 RECEPTORS IN RAT 106 6.1 I NTRODUCTION 106 6.2 M ATERIALS 108 6.3 M ETHODS 108 6.3.1 P REPARATION OF RAT BRAIN MEMBRANE SUSPENSIONS 108 3 6.3.2 D ETERMINATION OF KD OF [ H] MEPYRAMINE BINDING TO H1 RECEPTORS 109 6.3.3 D ETERMINATION OF K AND N CONCENTRATION RANGES FOR KI DETERMINATION 109 6.3.4 T OTAL BINDING (TB), NON -SPECIFIC BINDING (NB) AND SPECIFIC BINDING (SB) OF K AND N ATROPISOMERS TO H1 RECEPTORS 109 6.3.5 D ATA PROCESSING 110 6.4 R ESULTS 112 3 6.4.1 D ETERMINATION OF KD OF [ H] MEPYRAMINE BINDING TO H1 RECEPTORS 112 6.4.2 D ETERMINATION OF K AND N CONCENTRATION RANGES FOR KI DETERMINATION 113 3 6.4.3 TB OF [ H] MEPYRAMINE IN THE PRESENCE OF K AND N ATROPISOMERS 114 6.4.4 D ETERMINATION OF NB OF [3H] MEPYRAMINE IN THE PRESENCE OF K AND N ATROPISOMERS 115 3 6.4.5 SB OF [ H] MEPYRAMINE TO H1 RECEPTORS IN THE PRESENCE OF K AND N ATROPISOMERS 115 6.5 D ISCUSSION 117 CHAPTER 7 DETERMINATION OF TOTAL AND FREE BRAIN-TO-PLASMA RATIO OF K AND N ATROPISOMERS BY INJECTING
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