The effect of lipophilicity on the hepatobiliary properties of iminodiacetic acid derivatives in the conditions of hyperbilirubinemia |
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| Institution: | 1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, PO Box 146, Vojvode Stepe 450, 11000 Belgrade, Serbia;2. Medicines and Medical Devices Agency of Serbia, Vojvode Stepe 458, 11000 Belgrade, Serbia;3. Vinča Institute of Nuclear Sciences, University of Belgrade, PO Box 522, 11000 Belgrade, Serbia;1. 1st Department of Surgery, Semmelweis University, Budapest, Hungary;2. 2nd Department of Pathology, Semmelweis University, Budapest, Hungary;3. 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary;4. Tumor Progression Research Group, Joint Research Organization of the Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary;1. Beaujon Hospital, Assistance Publique Hôpitaux de Paris, Clichy, France;2. University Denis Diderot, Paris 7, France;1. Department of Gastroenterological Surgery, Graduate School of Life Sciences, Kumamoto University, Kumamoto, Japan;2. Medical Quality Management Center, Kumamoto University, Kumamoto, Japan;3. Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, Kurume University, Kurume, Japan;4. Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan;5. Department of Surgical Oncology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan;6. Clinical Research Center and Department of Surgery, National Hospital Organization Nagasaki Medical Center, Nagasaki, Japan;7. Department of Surgery, Saga University Faculty of Medicine, Saga, Japan;8. Department of Gastrointestinal and Hepato-Billiary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan;9. Department of Digestive Surgery, Breast and Thyroid Surgery, Graduate School of Medicine, Kagoshima University, Kagoshima, Japan;10. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;11. Department of Gastroenterological Surgery, Fukuoka University School of Medicine, Fukuoka, Japan;12. Department of Gastroenterological and Pediatric Surgery, Oita University Faculty of Medicine, Oita, Japan;13. Department of Surgical Oncology and Regulation of Organ Function, Miyazaki University School of Medicine, Miyazaki, Japan;14. Department of Surgery, Gastroenterology and Hepatology Center, Kitakyushu City Yahata Hospital, Kitakyushu, Japan;1. Vulnerability Biomarkers Unit, Division of Adult Psychiatry, Department of Mental Health and Psychiatry, University Hospitals of Geneva, Switzerland;2. Division of Addictology, Department of Mental Health and Psychiatry, University Hospitals of Geneva, Switzerland;3. Department of Psychiatry, University of Geneva, Switzerland |
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| Abstract: | The partition coefficients (log P) of theoretically possible alkyliodinated iminodiacetic acid (IDA) derivatives and commercial IDA derivatives were calculated using two computer programs: ChemSketch Log P and ChemOffice Ultra. Newly synthesized ligands (DIETHYLIODIDA and DIISOPROPYLIODIDA) with the highest calculated log P were labeled with technetium-99m. The biodistribution and the influence of bilirubin on their biokinetics were investigated in rats and compared to corresponding results for commercial 99mTc-BROMIDA. Log P of 99mTc-complexes of synthesized ligands were determined experimentally as well as the protein binding. In comparison to 99mTc-BROMIDA, 99mTc-DIETHYLIODIDA has: (a) better biliary excretion (2.76±0.15%ID/g versus 1.83±0.10%ID/g); (b) faster hepatic clearance (2.90±0.21%ID/g versus 7.47±0.70%ID/g) and decreased biliary excretion (for 14% versus 22%) in conditions of hyperbilirubinemia after 15 min. It is proved that 99mTc-DIISOPROPYLIODIDA has a prolonged hepatic transit time and decreased biliary excretion. |
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