Clinical study of the relationship between toxicity induced by pazopanib and pharmacokinetics

Research Project

Project/Area Number	16K08918
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Applied pharmacology
Research Institution	Showa University
Principal Investigator	Ishida Hiroo 昭和大学, 医学部, 講師 (00407404)
Project Period (FY)	2016-04-01 – 2020-03-31
Project Status	Completed (Fiscal Year 2019)
Budget Amount *help	¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000) Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000) Fiscal Year 2017: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000) Fiscal Year 2016: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Keywords	パゾパニブ / 薬物動態 / 有害事象 / トランスポーター / 遺伝子多型 / 悪性軟部腫瘍 / 軟部肉腫 / 臨床薬理学
Outline of Final Research Achievements	Pazopanib, a multi-target tyrosine kinase inhibitor, is mainly metabolized by hepatic enzymes such as cytochrome P450. Pazopanib is a substrate of OATP1B1, and It has been considered that organic anion-transporting polypeptide (OATP) 1B1 have significant role as hepatic drug-uptake transporter. We assessed the hepatic drug-uptake transporters related to pazopanib, and elucidated that pazopanib is transported from blood to hepatocyte by organic cation transporter (OCT) 1 than OATP1B1. Furthermore, we assessed the mechanism of drug-drug interaction between pazopanib and irinotecan. We revealed that pazopanib have a role of inhibition to UDP-glucuronosyl transferase (UGT) 1A1 and this induced increase of SN-38 concentration. On the other hand, it was clarified that pazopanib is not influenced hepatic uptake of SN-38 via OATP1B1.
Academic Significance and Societal Importance of the Research Achievements	OCT1には遺伝子多型の存在が報告されており、遺伝子多型の有無によりOCT1活性に個体差が生じ、結果として肝細胞内パゾパニブ濃度にも個体差が生じることが考えられる。パゾパニブによる肝機能障害とOCT1遺伝子多型の関連については今後検討が必要であるが、OCT1遺伝子多型がパゾパニブによる薬剤性肝障害のバイオマーカーとなる可能性がある。また、パゾパニブはUGT1A1阻害作用を有し、これによる薬物間相互作用を起こすことが明らかとなった。これからの結果はパゾパニブの臨床薬理学的特徴を明らかとし、より安全な治療の実践に寄与すると考える。