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Effects of steric hindrance and electron density of ester prodrugs on controlling the metabolic activation by human carboxylesterase |
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| Institution: | 1. Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Aoba-ku, Sendai, 980-8578, Japan;2. Division of Risk Assessment, National Institute of Health Sciences, Tonomachi 3-25-26, Kawasaki-ku, Kanagawa, 210-9501, Japan;3. Regulatory Science, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1, Tanabe-dori, Mizuho-ku, Nagoya, 467-8603, Japan;1. Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Japan;2. Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima-city, Japan;3. Shin Nippon Biomedical Laboratories, Ltd, Kainan, Wakayama, Japan;1. Discovery Technology Laboratories, Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Kanagawa, Japan;2. Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo, Japan;1. The Department of Clinical Pharmacology, Faculty of Medicine Jazan University, Saudi Arabia;2. American University of Health Sciences, Signal Hill, CA, USA;3. Ophthalmology, University of California, San Francisco, CA, USA;4. Ophthalmology, NYU Medical Center, NY, USA;1. Department of Urology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan;2. Department of Personalized Medicine and Preventive Healthcare Sciences, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan;3. Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Science, 2-5-1, Shikata-cho, Kita-ku, Okayama, 700-8558, Japan;1. Department of Pharmaceutics, School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, 061-0293, Japan;2. Department of Health and Environmental Sciences, School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido, 061-0293, Japan |
| Abstract: | Carboxylesterase (CES) plays an important role in the hydrolysis metabolism of ester–type drugs and prodrugs. In this study, we investigated the change in the hydrolysis rate of hCE1 by focusing on the steric hindrance of the ester structure and the electron density. For 26 kinds of synthesized indomethacin prodrugs, the hydrolytic rate was measured in the presence of human liver microsomes (HLM), human small intestine microsomes (HIM), hCE1 and hCE2. The synthesized prodrugs were classified into three types: an alkyl ester type that is specifically metabolized by hCE1, a phenyl ester type that is more easily metabolized by hCE1 than by hCE2, and a carbonate ester type that is easily metabolized by both hCE1 and hCE2. The hydrolytic rate of 1-methylpentyl (hexan–2–yl) ester was 10–times lower than that of 4–methylpentyl ester in hCE1 solution. hCE2 was susceptible to electron density of the substrate, and there was a difference in the hydrolysis rate of up to 3.5–times between p-bromophenyl ester and p-acetylphenyl ester. By changing the steric hindrance and electron density of the alkoxy group, the factors that change the hydrolysis rate by CES were elucidated. |
| Keywords: | Carboxylesterase Ester Drug metabolism Prodrug Substrate specificity ACE"} {"#name":"keyword" "$":{"id":"kwrd0040"} "$$":[{"#name":"text" "_":"angiotensin-converting-enzyme BPHB"} {"#name":"keyword" "$":{"id":"kwrd0050"} "$$":[{"#name":"text" "$$":[{"#name":"__text__" "_":"butyl "} {"#name":"italic" "_":"p"} {"#name":"__text__" "_":"-hydroxybenzoate CES"} {"#name":"keyword" "$":{"id":"kwrd0060"} "$$":[{"#name":"text" "_":"carboxylesterase DCC"} {"#name":"keyword" "$":{"id":"kwrd0070"} "$$":[{"#name":"text" "_":"dicyclohexylcarbodiimide DMAP"} {"#name":"keyword" "$":{"id":"kwrd0080"} "$$":[{"#name":"text" "_":"dimethylaminopyridine DMSO"} {"#name":"keyword" "$":{"id":"kwrd0090"} "$$":[{"#name":"text" "_":"dimethylsulfoxide EDC"} {"#name":"keyword" "$":{"id":"kwrd0100"} "$$":[{"#name":"text" "_":"1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hCE"} {"#name":"keyword" "$":{"id":"kwrd0110"} "$$":[{"#name":"text" "_":"human carboxylesterase HEPES"} {"#name":"keyword" "$":{"id":"kwrd0120"} "$$":[{"#name":"text" "_":"4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid HIM"} {"#name":"keyword" "$":{"id":"kwrd0130"} "$$":[{"#name":"text" "_":"human intestine microsomes HLM"} {"#name":"keyword" "$":{"id":"kwrd0140"} "$$":[{"#name":"text" "_":"human liver microsomes HPLC"} {"#name":"keyword" "$":{"id":"kwrd0150"} "$$":[{"#name":"text" "_":"high–performance liquid chromatography IR"} {"#name":"keyword" "$":{"id":"kwrd0160"} "$$":[{"#name":"text" "_":"infrared spectroscopy NMR"} {"#name":"keyword" "$":{"id":"kwrd0170"} "$$":[{"#name":"text" "_":"nuclear magnetic resonance ND"} {"#name":"keyword" "$":{"id":"kwrd0180"} "$$":[{"#name":"text" "_":"not detected PNPA"} {"#name":"keyword" "$":{"id":"kwrd0190"} "$$":[{"#name":"text" "$$":[{"#name":"italic" "_":"p"} {"#name":"__text__" "_":"-nitrophenyl acetate |
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