Pharmacokinetic studies of naproxen amides of some amino acid esters with promising colorectal cancer chemopreventive activity |
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| Affiliation: | 1. Dept. Med. Chem, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt;2. Dept. Pharm. Chem, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia;3. Dept. Pharmaceutics, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt;2. Dr B.R.Ambedkar Center for Biomedical Research, University of Delhi, India;1. Abdominal Transplant Surgery Unit, Fundación Valle de Lilí, Cali, Colombia;2. Centro de Investigaciones Clínicas, Fundación Valle del Lilí, Cali, Colombia;3. Centro para la Investigación en Cirugía Avanzada y Trasplantes, Universidad ICESI, Cali, Colombia;4. Hepatology Unit Fundación Valle de Lilí, Cali, Colombia;5. Transplant Infectious Diseases Unit, Fundación Valle de Lilí, Cali, Colombia;1. Division of Vascular & Interventional Radiology, Department of Radiology, Duke University Medical Center, Box 3808, 2301 Erwin Road, Durham, NC 27710;2. Division of Abdominal Imaging, Department of Radiology, Duke University Medical Center, Box 3808, 2301 Erwin Road, Durham, NC 27710;3. Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China;1. Dalian Sixth People’s Hospital, Dalian 116031, China;2. Personalized Treatment & Diagnosis Research Center, The First Affiliated Hospital of Liaoning Medical University and Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Jinzhou 121001, China;3. CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 116023 Dalian, China;4. Anorectal department, Xinhua Affiliated Hospital of Dalian University, 116033, China;5. Department of gastroenterology, Xinhua Affiliated Hospital of Dalian University, 116033, China;1. National Cancer Center Hospital, Tokyo, Japan;;2. Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan;;3. Saitama Medical Center, Jichi Medical University, Saitama, Japan;;4. Okayama University Hospital, Okayama, Japan;;5. National Hospital Organization Kyushu Medical Center, Fukuoka, Japan;;6. Hiroshima Red Cross Hospital & Atomic-bomb Survivors Hospital, Hiroshima, Japan;;7. Keio University School of Medicine, Tokyo, Japan;;8. The Institute of Medical Science, The University of Tokyo, Tokyo, Japan;;9. Tokai University Hospital, Isehara, Japan;;10. JA Aichi Konan Kosei Hospital, Konan, Japan;;11. Osaka City University, Osaka, Japan;;12. Saiseikai Maebashi Hospital, Gunma, Japan;;13. Kobe City Medical Center General Hospital, Kobe, Japan;;14. Hokkaido University Hospital, Sapporo, Japan;;15. Shimane Prefectural Central Hospital, Izumo, Japan;;16. Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan;;17. Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan;;18. St. Luke''s International Hospital, Tokyo, Japan |
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| Abstract: | Naproxen (nap) is belonging to Non-steriodal anti-inflammatory drugs (NSAIDs) group of drugs that characterized by their free carboxylic group. The therapeutic activity of nap is usually accompanied by GI untoward side effects. Recently synthesized naproxen amides of some amino acid esters prodrugs to mask the free carboxylic group were reported. Those prodrugs showed a promising colorectal cancer chemopreventive activity. The current study aims to investigate the fate and hydrolysis of the prodrugs kinetically in different pH conditions, simulated gastric and intestinal fluids with pHs of 1.2, 5.5 and 7.4 in vitro at 37 °C. The effect of enzymes on the hydrolysis of prodrugs was also studied through incubation of these prodrugs at 37 °C in human plasma and rat liver homogenates. The pharmacokinetic parameters of selected prodrugs and the liberated nap were studied after oral and intraperitoneal administration in male wistar rats. The results showed the hydrolysis of naproxen amides of amino acid esters to nap through two steps first by degradation of the ester moiety to form the amide of nap with amino acid and the second was through the degradation of the amide link to liberate nap. The two reactions were followed and studied kinetically where K1 and K2 (rate constants of degradation) is reported. The hydrolysis of prodrugs was faster in liver homogenates than in plasma. The relative bioavailability of the liberated nap in vivo was higher in case of prodrug containing ethyl glycinate moiety than that occupied l-valine ethyl ester moiety. Each of nap. prodrugs containing ethyl glycinate and l-valine ethyl ester moieties appears promising in liberating nap, decreasing direct GI side effect and consequently their colorectal cancer chemopreventive activity. |
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| Keywords: | Naproxen amides Prodrugs Bioavailability Degradation kinetics Psudo first-order kinetics |
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