Consideration of Two Cases with Marked PT-INR Elongation by Interaction between High-dose Acetaminophen and Warfarin

Abstract

Acetaminophen is approved up to 4,000 mg per day as an analgesic agent in Japan and displays analgesic effects depending on dosage. On the other hand, acetaminophen has some interactional effects. The mechanism of the interaction between acetaminophen and warfarin has not been elucidated, and no interactional cases have been reported in Japan either. However, two cases of marked PT-INR elongation were recognized by two inpatients in our hospital, Japanese males in their 50s and 60s who were treated with concurrent chemoradiotherapy using 70 Gy radiotherapy delivered as 2 Gy daily and triweekly 100 mg/m 2 cisplatin, that had been prescribed both drugs. Each PT-INR lapsed into loss of control; the maximum for one was more than 20 which was unmeasurable and for the other, 9.48, given vitamin K2 (VK2) immediately was antagonistic to warfarin. Concomitant drugs of warfarin were promptly checked again to see if it was related to the plasma protein binding ratio and hepatic cytochrome P450 inhibition reaction. Furthermore, each liver function test was also normal. As a result of consideration on these two, the dosage of acetaminophen has possible implications. It could be caused by the active metabolite of acetaminophen, NAPQI (N-acetyl-para-benzoquinone imine), as reported by basic research of VK cycle inhibitory action; however, the mechanism is not completely clear yet so future research is required to clarify this point. In any case, it is necessary to regularly measure PT-INR through the combination of warfarin and acetaminophen. Key words-high-dose acetaminophen, warfarin, drug interactions, PT-INR, active metabolite, NAPQI 緒 言 現在，数多くの薬剤が臨床で使用されており， 各薬剤が適正な薬効を発揮し副作用も最小限に留 められるように薬の専門家である薬剤師が介入す べきところは多い．患者に提供される薬物療法の 質を薬学的な知識を活用し担保することは薬剤師 の重要な専門性の 1 つである．そのため，薬物相 互作用に関する研究は数多くなされており，これ らの研究成果は臨床業務に広く活用されている． しかし，薬物相互作用の機序が明らかになってい ないものが多い． このうちの 1 つとして， ワルファ リンとアセトアミノフェンの相互作用が挙げられ る．ワルファリンの作用機序は，ビタミン K 作 用に拮抗し肝臓におけるビタミン K 依存性血液 凝固因子（プロトロンビン，第 7，第 9，および 第 10 因子）の生合成を抑制して抗凝血・抗血栓 効果を示す（ワーファリン ® 錠添付文書，エーザ イ株式会社，2016 年 10 月改訂）とされており， 効 果 の 指 標 と し て prothrombin time-international