2023-04-24 ワシントン州立大学(WSU)
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ジクロフェナクは、関節炎に関連する痛みや炎症を抑えるために使用されます。米国では、2013年まで市販薬として入手可能でしたが、その後、薬物が心臓障害を引き起こすという報告があったため、処方箋専用薬として制限されました。米国では年間1000万件以上の処方箋が書かれています。これは世界中で最も広く使用されている非ステロイド性抗炎症薬の1つです。
この新しい研究では、WSUの研究者は、ヒトの肝臓と腸のサンプルをコンピューターベースのモデリングとともに使用して、この酵素が他の関連酵素と比較してジクロフェナク代謝に寄与する程度を定量化しました。彼らはそれが主要なプレーヤーであることを発見し、低レベルのUGT2B17酵素がジクロフェナクの使用に関連する心臓損傷の原因である可能性があるという考えを支持しました。
<関連情報>
- https://news.wsu.edu/press-release/2023/04/24/study-points-to-cause-of-safety-concerns-in-widely-used-painkiller-diclofenac/
- https://ascpt.onlinelibrary.wiley.com/doi/abs/10.1002/cpt.2907
多型UGT2B17によるジクロフェナクの腸内代謝は、集団間で大きく変動する薬物動態と安全性に相関する Intestinal metabolism of diclofenac by polymorphic UGT2B17 correlates with its highly variable pharmacokinetics and safety across populations
Deepak Ahire, Scott Heyward, Bhagwat Prasad
Clinical Pharmacology & Therapeutics Published: 12 April 2023
DOI:https://doi.org/10.1002/cpt.2907
Abstract
Although the United States and Europe have shifted to the prescription use of diclofenac due to several serious incidences of cardiotoxicity, it is one of the most commonly used over-the-counter (OTC) medicine in major parts of the world. We elucidated the quantitative and tissue-specific contribution of uridine diphosphate-glucuronosyltransferases 17 (UGT2B17) in diclofenac metabolism and pharmacokinetics. UGT2B17 is one of most deleted genes in humans with the gene deletion frequency ranging from ~20% in Caucasians to 90% in Japanese. The human intestinal and liver microsomes isolated from the high-UGT2B17 expressing individuals showed 21- and 4-fold greater rate of diclofenac glucuronide (DG) formation than in the null-UGT2B17 carriers, respectively. The greater contribution of intestinal UGT2B17 was confirmed by a strong correlation (R= 0.78, p<0.001) between UGT2B17 abundance and DG formation in individual intestinal microsomes (n=14). However, because UGT2B17 is a minor UGT isoform in the liver, DG formation rate correlated better with the expression of UGT2B7. The proteomics-informed physiologically-based pharmacokinetic model explains the reported higher exposure of diclofenac in females consistent with ~3-fold lower expression of UGT2B17. Similarly, our predictions also corroborate with the reported higher exposure and lower standard clinical dose of diclofenac in Japanese population. Therefore, UGT2B17 mediated metabolism of oral diclofenac is a concern, especially in the developing countries where it is still used as an OTC drug. The ontogeny data of UGTs in human hepatocytes can be utilized in developing PBPK models for predicting pharmacokinetics in pediatric population.
