Okuda H, Nishiyama T, Ogura K, Nagayama S, Ikeda K, Yamaguchi S, Nakamura Y, Kawaguchi Y, Watabe T
Department of Drug Metabolism and Molecular Toxicology, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Japan.
Drug Metab Dispos. 1997 May;25(5):270-3.
Rats were orally co-administered sorivudine (SRV: 1-beta-D-arabinofuranosyl-(E)-5-(2-bromovinyl)uracil), a new oral antiviral drug for herpes zoster, with the oral anticancer drug tegafur (FT: 1-(2-tetrahydrofuryl)-5-fluorouracil as a prodrug of 5-fluorouracil (5-FU) once daily to investigate a toxicokinetic mechanism of 15 Japanese patients' deaths recently caused within a brief period by the drug interaction of these drugs. All the rats showed extremely elevated levels of 5-FU in plasma and tissues, including bone marrow and small intestine, and died within 10 days, whereas the animals given the same dose of SRV or FT alone were still alive over 20 days without any appreciable toxic symptom. Before their death, there was marked damage of bone marrow, marked atrophy of intestinal membrane mucosa, marked decreases in white blood cells and platelets, diarrhea with bloody flux, and severe anorexia as reported with the Japanese patients. Data obtained by in vivo and in vitro studies strongly suggested that (E)-5-(2-bromovinyl)uracil generated from SRV by gut flora was reduced in the presense of NADPH to a reactive form by hepatic dihydropyrimidine dehydrogenase (DPD), a key enzyme determining the tissue 5-FU levels, bound covalently to DPD as a suicide inhibitor, and markedly retarded the catabolism of 5-FU.
给大鼠每日一次口服联合给予索立夫定（SRV：1-β-D-阿拉伯呋喃糖基-(E)-5-(2-溴乙烯基)尿嘧啶），一种用于带状疱疹的新型口服抗病毒药物，与口服抗癌药物替加氟（FT：1-(2-四氢呋喃基)-5-氟尿嘧啶，作为5-氟尿嘧啶（5-FU）的前体药物），以研究近期15名日本患者因这两种药物相互作用在短时间内死亡的毒代动力学机制。所有大鼠血浆和包括骨髓及小肠在内的组织中的5-FU水平均极度升高，并在10天内死亡，而单独给予相同剂量SRV或FT的动物在20多天后仍存活，无任何明显毒性症状。在它们死亡前，出现了如日本患者所报道的骨髓严重损伤、肠黏膜显著萎缩、白细胞和血小板显著减少、血性腹泻以及严重厌食。体内和体外研究获得的数据强烈表明，肠道菌群从SRV产生的(E)-5-(2-溴乙烯基)尿嘧啶在NADPH存在的情况下被肝脏二氢嘧啶脱氢酶（DPD，一种决定组织5-FU水平的关键酶）还原为一种活性形式，作为自杀性抑制剂与DPD共价结合，并显著阻碍5-FU的分解代谢。
