A study on concomitant drugs to improve the analgesic effects and decrease the side effects of morphine

2015 Fiscal Year Final Research Report

• Project/Area Number: 25460227
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Meiji Pharmaceutical University
• Principal Investigator: Kagaya Hajime 明治薬科大学, 薬学部, 教授 (00642969)
• Co-Investigator(Kenkyū-buntansha): UESAWA Yoshihiro 明治薬科大学, 薬学部, 准教授 (90322528) ; NOZAWA Reiko (ISHII Reiko) 明治薬科大学, 薬学部, 講師 (60257144)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: モルヒネ / 併用薬 / 定量的構造活性相関 / 機械学習 / 血液脳関門 / トランスポーター / 鎮痛効果

Outline of Final Research Achievements

Morphine is a substrate of MDR1, which is expressed in the BBB and regulates the excretion of drugs from the brain. On the other hand, morphine-6-glucuronide (M-6-G), an active metabolite, is a substrate of OATP. Therefore, seed compounds for concomitant drugs with morphine were investigated to identify compounds that can prohibit the elimination of morphine by MDR1 and allow the uptake of M-6-G by OATP. Compounds with properties similar to OATP1A2 substrates and MDR1 inhibitors were extracted from drug interaction databases. Structural properties were calculated based on chemical structures to construct QSAR models. The models were constructed using machine learning techniques, such as deep-learning. The models for both transporters were adopted to locate seed compounds from a chemical compound database to ensure that the morphine reached the brain effectively. These models enabled the selection of compounds with the dual properties of high MDR1 inhibition and low OATP substrate.

Free Research Field

緩和医療薬学