University of Kentucky UKnowledge University of Kentucky Doctoral Dissertations Graduate School 2010 OPIOID-CANNABINOID CODRUGS WITH ENHANCED ANALGESIC AND PHARMACOKINETIC PROFILE Harpreet Kaur Dhooper University of Kentucky, [email protected] Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Dhooper, Harpreet Kaur, "OPIOID-CANNABINOID CODRUGS WITH ENHANCED ANALGESIC AND PHARMACOKINETIC PROFILE" (2010). University of Kentucky Doctoral Dissertations. 98. https://uknowledge.uky.edu/gradschool_diss/98 This Dissertation is brought to you for free and open access by the Graduate School at UKnowledge. It has been accepted for inclusion in University of Kentucky Doctoral Dissertations by an authorized administrator of UKnowledge. For more information, please contact [email protected]. ABSTRACT OF DISSERTATION Harpreet Kaur Dhooper College of Arts & Sciences University of Kentucky 2010 OPIOID-CANNABINOID CODRUGS WITH ENHANCED ANALGESIC AND PHARMACOKINETIC PROFILE _________________________________________ ABSTRACT OF DISSERTATION _________________________________________ A dissertation submitted in partial fulfillment of the requirement for the degree of Doctor of Philosophy in the College of Arts & Sciences at the University of Kentucky By Harpreet Kaur Dhooper Lexington, Kentucky Director: Dr. Peter A. Crooks, Professor of Pharmaceutical Sciences Lexington, Kentucky 2010 Copyright © Harpreet Dhooper 2010 ABSTRACT OF DISSERTATION OPIOID-CANNABINOID CODRUGS WITH ENHANCED ANALGESIC AND PHARMACOKINETIC PROFILE The central hypothesis of the dissertation is that “the design and synthesis of a codrug of an opiate and a cannabinoid can be achieved which is stable in the gastrointestinal tract and shows a superior pharmacological and pharmacokinetic profile when compared to a physical mixture of the two parent drugs.” To prove the hypothesis, a series of novel codrugs were prepared by conjugation of the opiate drug codeine with ∆9- tetrahydrocannabinol (∆9-THC), cannabidiol, abn-cannabidiol and an opiate prodrug 3-O- acetylmorphine with ∆9-THC. Codeine-cannabinoid codrugs were evaluated for analgesic activity in the rat after oral administration. The Cod-THC codrug showed greater effectiveness as well as prolonged pain management properties as compared to the parent drugs. The stability of Cod-THC codrug in aqueous solutions from pH 1-9, in simulated gastrointestinal fluids, in brain homogenate and the hydrolysis of the carbonate ester linkage in rat plasma suggested that after oral administration, the codrug would be absorbed intact from the GI tract and then hydrolyze in the plasma to generate both parent drugs. The enzymes present in rat brain homogenate were incapable of cleaving the codrug into the parent drugs. The pharmacokinetic profiles of the Cod-THC codrug and an equimolar physical mixture of the parent drugs were evaluated in rats. The plasma concentrations of codeine and∆ 9- THC were much higher after codrug administration compared to the plasma concentrations of these drugs after oral administration of an equimolar physical mixture. The parent drugs were also present in the plasma for longer period of time compared to the physical mixture, probably due to the sustained release of the parent drugs from codrug in the plasma. The concentrations of codeine and Δ9-THC were much higher in rat brain after oral administration of the Cod-THC codrug as compared to brain concentrations of these drugs after oral administration of the physical mixture. Thus, the design and synthesis of an opiate and a cannabinoid codrug was achieved which was stable in the gastrointestinal tract, showed enhanced analgesic effects as compared to the parent drugs, and also showed a superior pharmacokinetic profile when compared to a physical mixture or the two parent drugs. KEYWORDS: Opioid, Cannabinoid, Codrug, Antinociception, Pharmacokinetics Harpreet Dhooper Date OPIOID-CANNABINOID CODRUGS WITH ENHANCED ANALGESIC AND PHARMACOKINETIC PROFILE By Harpreet Kaur Dhooper ____________________________________ Director of Dissertation ____________________________________ Director of Graduate Studies ____________________________________ Date RULES FOR THE USE OF DISSERTATIONS Unpublished dissertation submitted for the Doctor’s degree and deposited in the University of Kentucky Library are as a rule open for inspection, but are to be used only with due regard to the rights of the authors. Bibliographical references may be noted, but quotations and summaries of parts may be published only with the permission of the author, and with the usual scholarly acknowledgement. Extensive copying or publication of the dissertation in whole or in part also requires the consent of the Dean of the Graduate School of the University of Kentucky. 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Name Date ________________________________________________________________________ ________________________________________________________________________ ________________________________________________________________________ ________________________________________________________________________ ________________________________________________________________________ ________________________________________________________________________ ________________________________________________________________________ ________________________________________________________________________ ________________________________________________________________________ ________________________________________________________________________ ________________________________________________________________________ DISSERTATION Harpreet Kaur Dhooper College of Arts and Sciences University of Kentucky 2010 OPIOID-CANNABINOID CODRUGS WITH ENHANCED ANALGESIC AND PHARMACOKINETIC PROFILE ________________________________________ DISSERTATION ________________________________________ A dissertation submitted in partial fulfillment of the requirement for the degree of Doctor of Philosophy in the College of Arts & Sciences at the University of Kentucky By Harpreet Kaur Dhooper Lexington, Kentucky Director: Dr. Peter A. Crooks, Professor of Pharmaceutical Sciences Lexington, Kentucky 2010 Dedication To my parents ACKNOWLEDGEMENTS Foremost, I would like to express my sincere gratitude to my advisor Dr. Peter A. Crooks for the continuous support of my Ph.D study and research, for his patience, motivation, enthusiasm, and immense knowledge. His guidance helped me in all the time of research and writing of this thesis. I could not have imagined having a better advisor and mentor for my Ph.D study. I would like to thank all my advisory committee members, Dr. Stephen Testa, Dr. Abeer Al-Ghananeem, Dr. Joseph Holtman, Dr. Boyd Haley and Dr. Mark Watson for their time, and suggestions in designing some of the experiments. I am grateful to Dr. Zaineb Albayati and Dr. Elzbeita Wala for helping me with all the animal work. I thank Dr. Malkawi for his help with the HPLC studies of the drugs. I would like to thank Dr. Jamie Horn and John May for their help with the LC-MS/MS studies. I am thankful to Dr. Peter Wedlund for helping me with pharmacokinetics. I would also like to thank my friend, Ujjwal Chakraborty for his constant support. He has always been a constant source of encouragement during my graduate study. Additionally, I am very grateful for the friendship of all of the members of Crooks’ research group with whom I worked closely and puzzled over many problems. I want to thank my father-in-law Dr. Surjit Singh Dhooper without whom I would never have been able to achieve so much. He has always been one of my best counselors. I also want to thank my mother-in-law, my husband and my kids, Mantegh and Sachleen for their moral suppo rt. I am extremely thankful to my parents, the reason for my existence. I would like to dedicate this dissertation research to them. Without their sacrifice, blessings and encouragement it would have been impossible to reach this stage. I have no suitable words that can fully describe their everlasting love to me. Although they are no longer with me, they are forever remembered. I am sure they share our joy and happiness in the heaven. The support of my brother and sisters is also greatly appreciated. III TABLE OF CONTENTS Acknowledgements III List of Figures VIII List of Schemes XIV List of Tables XVI Chapter 1. Objects of the Study and Literature Review 1.1 Hypothesis 1 1.2 Overall Aim 1 1.3 Methodology to be utilized in this study 2 1.4 Literature Review 1.4.1 Codrugs/Hybrid Drugs 3 1.4.2 Marketed Codrug 9 1.4.3 Codrug for the Treatment of Proliferative Diabetic Retinopathy 10 1.4.4 Codrug for the Simultaneous Treatment of Alcohol Abuse and Tobacco Dependence 15 1.4.5 L-DOPA Codrugs 23 1.5 Codrug strategy in pain management 1.5.1 Opioids and Cannabinoids 28 1.5.2 Pharmacokinetics and Pharmacodynamics of Opioids 28 1.5.3 Pharmacokinetics and Pharmacodynamics of Cannabinoids 31 Chapter 2. Synthesis of Codrugs and Parent drugs 2.1 Synthesis of ∆9-Tetrahydrocannabinol (∆ 9-THC) 35 2.2 Synthesis of (-)-Cannabidiol (CBD) 36 2.3 Codeine-∆9-Tetrahydrocannabinol (Cod-THC) Codrug Synthesis 47 2.4 Synthesis of the Codeine-(-)-Cannabidiol (Cod-CBD) 60 IV 2.5 Synthesis of the Codeine-abnCannabidiol (Cod-abnCBD) 61 2.6 Synthesis of the 3-O-acetylmorphine-∆9-tetrahydrocannabinol (AcMor-THC) 63 2.7 Experimental Section 7 Chapter 3. The Analgesic activities of Codrugs and