Effect of deuteration on the single dose pharmacokinetic properties and postoperative analgesic activity of methadone |
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| Institution: | 1. Maternal-Fetal Pharmacology and Bio-Development Laboratories, Department of Obstetrics & Gynecology, University of Texas Medical Branch, Galveston, TX, 77555, USA;2. Department of Neuroscience, Cell Biology and Anatomy, University of Texas Medical Branch, Galveston, TX, 77555, USA;1. Joint Faculty of Veterinary Medicine, Kagoshima University, Kagoshima, Japan;2. Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd., Kainan, Japan;3. Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Japan;1. Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Tokyo, Japan;2. Advanced Research Center for Innovations in Next-Generation Medicine, Tohoku University, Sendai, Japan;3. Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan;4. Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan;5. Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan;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, Kawasaki, 210-9501, Japan;3. Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526 Japan;4. Department of Drug Metabolism and Pharmacokinetics, Nonclinical Research Center, Tokushima Research Institute, Otsuka Pharmaceutical Co, Ltd, 463-10 Kagasuno, Kawauchi-cho, Tokushima, 771-0192, Japan;1. Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand;2. Unit of Excellence on Pharmacogenomic Pharmacokinetic and Pharmacotherapeutic Researches (UPPER), School of Pharmaceutical Sciences, University of Phayao, Phayao, Thailand;3. Pharmacy Unit, Udon Thani Hospital, Udon Thani, Thailand;4. Division of Dermatology, Department of Internal Medicine, Khon Kaen Hospital, Khon Kaen, Thailand;5. Pharmacy Department, Khon Kaen Hospital, Khon Kaen, Thailand;6. Pharmacy Unit, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand;1. Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, 230032, PR China;2. Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, Institute for Liver Diseases of Anhui Medical University, School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China;3. The Grade 3 Pharmaceutical Chemistry Laboratory of State Administration of Traditional Chinese Medicine, Hefei, 230032, PR China;4. Center for Scientific Research of Anhui Medical University, Hefei, 230032, PR China;5. Hefei Kaifan Analytical Technology Co., Ltd., Hefei, 230051, PR China;1. Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshidashimoadachi-cho, Sakyo-ku, Kyoto, 606-8501, Japan;2. Department of Micro Engineering, Graduate School of Engineering, Kyoto University, Nishikyo-ku, Kyoto, 615-8540, Japan;3. Institute for Glyco-core Research (iGCORE), Gifu University, 1-1 Yanagido, Gifu-shi, Gifu, 501-1193, Japan |
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| Abstract: | Although methadone is effective in the management of acute pain, the complexity of its absorption-distribution-metabolism-excretion profile limits its use as an opioid of choice for perioperative analgesia. Because deuteration is known to improve the pharmacokinetic, pharmacodynamic and toxicological properties of some drugs, here we characterized the single dose pharmacokinetic properties and post-operative analgesic efficacy of d9-methadone.The pharmacokinetic profiles of d9-methadone and methadone administered intravenously to CD-1 male mice revealed that deuteration leads to a 5.7- and 4.4-fold increase in the area under the time-concentration curve and maximum concentration in plasma, respectively, as well as reduction in clearance (0.9 ± 0.3 L/h/kg vs 4.7 ± 0.8 L/h/kg). The lower brain-to-plasma ratio of d9-methadone compared to that of methadone (0.35 ± 0.12 vs 2.05 ± 0.62) suggested that deuteration decreases the transfer of the drug across the blood-brain barrier. The estimated LD50 value for a single intravenous dose of d9-methadone was 2.1-fold higher than that for methadone. Moreover, d9-methadone outperformed methadone in the efficacy against postoperative pain by primarily activating peripheral opioid receptors. Collectively, these data suggest that the replacement of three hydrogen atoms in three methyl groups of methadone altered its pharmacokinetic properties, improved safety, and enhanced its analgesic efficacy. |
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| Keywords: | Deuteration Pharmacokinetic Metabolism Postoperative pain |
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