Prediction of opioid analgesics pharmacokinetics using the biomarkers of drug metabolizing enzyme activity in cancer patients

• Project/Area Number: 17K08410
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical pharmacy
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: NAITO TAKAFUMI 浜松医科大学, 医学部附属病院, 特任准教授 (80422749)
• Co-Investigator(Kenkyū-buntansha): 川上 純一 浜松医科大学, 医学部附属病院, 教授 (50272539)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: オピオイド / がん性疼痛 / 薬物動態 / 薬物代謝酵素 / 遺伝子多型 / 炎症 / バイオマーカー / CYP3A4 / CYP2D6 / 血清バイオマーカー / 4β水酸化コレステロール / マイクロRNA / CYP3A4/5 / エピジェネティック因子 / CYP3A / 炎症性サイトカイン / 薬物代謝 / 個別化薬物療法

Outline of Final Research Achievements

Cancer patients have a large variation in clinical responses to opioid analgesics. Their variations are partially associated with the individual pharmacokinetics of opioid analgesics under the cancer states. To date, it has been difficult to predict the pharmacokinetics of opioid analgesics using the genetic polymorphisms of CYP3A for each cancer patient. This study evaluated the relationships of genetic and epigenetic factors, inflammatory markers, and endogenous markers of CYP3A activity with the pharmacokinetics of CYP3A substrates including oxycodone and tramadol in cancer patients. The present study revealed the pharmacokinetic predictability of opioid analgesics using the several candidate endogenous markers related to CYP3A activity in cancer patients.

Academic Significance and Societal Importance of the Research Achievements

本研究成果の学術的意義として、薬物代謝酵素の遺伝情報とともに、がん患者のエピジェネティクスな変化、サイトカインなどの炎症関連因子の変化、薬物代謝酵素活性の内因性マーカーの変化を指標としたオピオイドの体内動態の予測法の確立に繋がる。
本研究成果の社会的意義として、がん患者における内因性マーカーを利用したオピオイドの体内動態の予測はがん病期ごとのオピオイドの選択や除痛療法のテーラーメイド化の実現に貢献でき、がん患者のQOLの向上が期待できる。

Research Products

• [Journal Article] A reversed-phase mode LC-MS/MS method using a polysaccharide chiral selector for simultaneous quantitation of each enantiomer of tramadol and its metabolites in human plasma and evaluation of CYP-mediated stereoselective demethylation. (2020)
  • Author(s): Suzuki K, Naito T, Tanaka H, Yamada Y, Itoh K, Kawakami J.
  • Journal Title: Ther Drug Monit Volume: － Issue: 3 Pages: 503-511
  • DOI: 10.1097/ftd.0000000000000707
  • Peer Reviewed
• [Presentation] 頭頸部がん患者におけるトラマドール及び代謝物の光学異性体の血中動態とCYP2D6のactivity scoreとの関係解析. (2020)
  • Author(s): 鈴木光路, 内藤隆文, 田中達也, 山田康秀, 伊藤邦彦, 川上純一.
  • Organizer: 第140回日本薬学会年会
• [Presentation] An enantiomeric quantitation of tramadol and its metabolites in human plasma and evaluation of cytochrome P450-mediated stereoselective demethylation. (2019)
  • Author(s): Suzuki K, Naito T, Tanaka H, Yamada Y, Itoh K, Kawakami J.
  • Organizer: The 120th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics (ASCPT2019)
  • Int'l Joint Research