In 1993, eighteen acute deaths occurred in Japanese patients who received a clinical dose of the new oral antiviral drug, sorivudine (SRV: 1-β-D-arabinofuranosyl-(E)-5-(2-bromovinyl) uracil), for herpes zoster. That was only within 40 days after SRV was approved by the Japanese government for clinical use. All patients who died had been receiving one of 5-fluorouracil (5-FU) prodrugs for anticancer chemotherapy. None of patients who received SRV alone or SRV and anti-cancer drugs other than 5-FU or its prodrugs, died or suffered from toxic symptoms. A toxicokinetic study using rats orally given simultaneously with SRV and the 5-FU prodrug, tegafur (FT: 1-(2-tetrahydrofuryl)-5-fluorouracil), once a daily, strongly suggested that the patients died from a marked increase in tissue 5-FU levels by the mechanismbased inhibition of hepatic dihydropyrimidine dehydrogenase (DPD), with (E)-2-(5-bromovinyl) uracil (BVU), a metabolite of SRV by gut flora. DPD is a rate-limiting enzyme in the catabolism of 5-FU in the rat and the human. All rats showed a marked increase in the 5-FU level in plasma and tissues such as intestines and bone marrow from the first day of the experiment and died within 10 days after the repeated administration of SRV and FT. Before the death, the rats showed severe diarrhea with bloody flux and marked decreases in white blood cell and platelet counts as had been reported for the patients.
In the presence of NADPH, DPD isolated from the untreated rat liver and human recombinant DPD were completely inactivated and radiolabeled by [¹⁴C] BVU. Two radioactive peptides were isolated by HPLC from a tryptic digest of the radiolabeled human DPD. Amino acid sequencing indicated that the two peptides were derived from a common regional sequence of the DPD, which was in the potential pyrimidine-binding domain located at positions 665-686 of the enzyme subunit. Only the Cys residue at a position of 671 in the DPD was found to be radiolabeled and unidentified by the amino acid sequencing of the tryptic fragments. MALDI-TOF MS analysis indicated that the SH of Cys671 formed a sulfide bond by the reaction with the allyl bromide type of reactive metabolite, 5-(2-bromovinylydeny) uracil, yielded in the DPD subunit. The sulfide bond formation appears to make it impossible for the DPD to interact with the 5-FU through the substrate-binding domain. Therefore, the patients who died from the drug-drug interactions were most likely to become extremely poor metabolizers for 5-FU by the mechanism-based inhibition of DPD with BVU from SRV.

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トラマール^®カプセル25 mg・50 mg（有効成分：トラマドール塩酸塩）は，「軽度から中等度の疼痛を伴う各種癌における鎮痛」の効能・効果で2010年7月に承認された．トラマドール塩酸塩はμ-オピオイド受容体を介する作用，ならびにノルアドレナリンやセロトニンの再取り込み系を抑制する作用を有し，これらが抗侵害作用の主たる作用機序と考えられている．軽度から中等度のがん疼痛患者を対象とした臨床試験において，トラマドールは100～300 mg/日の用量範囲で鎮痛効果を有した．また，トラマドール100～300 mg/日のモルヒネに対する効力比は0.200であり，モルヒネ等の強オピオイド鎮痛薬に変更する際には，トラマドールの定時投与量の1/5用量がモルヒネの初回投与量の目安となることが示唆された．さらに，トラマドールが長期にわたり疼痛制御が可能であることを確認するとともに，依存性形成を疑わせる結果は認められなかった．安全性についてはレスキュー・ドーズを含めて400 mg/日までの忍容性を確認した．トラマドールの副作用発現率は，モルヒネに忍容性のある患者を対象とした第III相二重盲検クロスオーバー試験では，モルヒネに比して差はなかったが，オピオイド鎮痛薬未投与の患者を対象とした第III相二重盲検並行群間比較試験では，モルヒネに比して低く，主な副作用は便秘，悪心，傾眠ならびに嘔吐であった．このうち，便秘の発現率およびその程度はいずれもモルヒネより低かった．以上の事から，トラマドールは非オピオイド鎮痛薬では鎮痛効果不十分ながん疼痛患者にオピオイド鎮痛薬による治療を開始する際の導入薬として，治療上の新たな選択肢の1つになることが期待される．

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