Bonate Peter L, Beyerlein David, Crawford Jennifer, Roth Stephanie, Krumbholz Roy, Schmid Steve
Genzyme Corporation, 4545 Horizon Hill Blvd, San Antonio, TX 78229, USA.
AAPS J. 2007 Dec 14;9(3):E378-87. doi: 10.1208/aapsj0903045.
The pharmacokinetics of tasidotin (ILX651), a depsipeptide currently in phase II for the treatment of advanced solid tumors, and tasidotin-C-carboxylate, the main metabolite, were characterized in male nude mice implanted with LOX tumors, which are sensitive to tasidotin, or H460 tumors, which are resistant to tasidotin. The pharmacokinetics of tasidotin and its metabolites were characterized after single-dose administration of tasidotin (20 and 120 mg/kg), tasidotin-C-carboxylate (150 mg/kg), or tasidotin (53 mg/kg) in the presence and absence of Z-prolyl prolinal (5 mg/kg administered 1 hour prior to tasidotin administration), a competitive antagonist of prolyl oligopeptidase, the enzyme responsible for the metabolism of tasidotin to tasidotin-C-carboxylate. A secondary study was done comparing tumor growth in tasidotin-treated mice with implanted LOX tumors in the presence and absence of Z-prolyl-prolinal. After tasidotin administration, the pharmacokinetics of tasidotin and tasidotin-C-carboxylate were similar in plasma and tumors in LOX- and H460-implanted mice, indicating the resistance was not due to pharmacokinetic factors. Tumor carboxylate concentrations were much higher than in plasma after tasidotin administration. The metabolite appeared to contribute approximately 17% to 33% to the total exposure in LOX tumors and 20% to 49% in H460 tumors but <5% in plasma. Less than 5% of the administered tasidotin dose was converted to tasidotin-C-carboxylate, with no apparent differences between LOX- and H460-treated animals. The presence of Z-prolyl-prolinal decreased the amount of tasidotin converted to tasidotin-C-carboxylate from 5.5% to 0.90%, a reduction of almost 80%. After tasidotin-C-carboxylate administration, the half-life was on the order of minutes compared with hours when observed after tasidotin administration. Tasidotin-C-carboxylate elimination was not dependent on tasidotin pharmacokinetics, suggesting that the rate of efflux from cells into plasma was the rate-limiting step in its elimination. Tasidotin-C-carboxylate was also further metabolized to desprolyl-tasidotin-C-carboxylate, although the metabolite ratios were <10%. Pretreatment with Z-prolyl-prolinal completely abolished the antitumor activity of tasidotin, indicating that the metabolite is the main moiety responsible for activity and that, despite tasidotin itself having activity in vitro, tasidotin is acting mainly as a prodrug.
他西多丁（ILX651）是一种目前处于治疗晚期实体瘤II期试验阶段的缩肽，其主要代谢产物他西多丁-C-羧酸盐在植入对他西多丁敏感的LOX肿瘤或对他西多丁耐药的H460肿瘤的雄性裸鼠体内的药代动力学特征得到了研究。在给予他西多丁（20和120 mg/kg）、他西多丁-C-羧酸盐（150 mg/kg）或他西多丁（53 mg/kg）单剂量后，以及在存在和不存在Z-脯氨酰脯氨醛（在给予他西多丁前1小时给予5 mg/kg）的情况下，对他西多丁及其代谢产物的药代动力学进行了表征。Z-脯氨酰脯氨醛是脯氨酰寡肽酶的竞争性拮抗剂，脯氨酰寡肽酶是负责将他西多丁代谢为他西多丁-C-羧酸盐的酶。还进行了一项二级研究，比较了在存在和不存在Z-脯氨酰脯氨醛的情况下，他西多丁治疗的植入LOX肿瘤的小鼠的肿瘤生长情况。给予他西多丁后，在植入LOX和H460肿瘤的小鼠的血浆和肿瘤中，他西多丁和他西多丁-C-羧酸盐的药代动力学相似，表明耐药性不是由药代动力学因素引起的。给予他西多丁后，肿瘤中的羧酸盐浓度远高于血浆中的浓度。该代谢产物似乎对LOX肿瘤中的总暴露量贡献约17%至33%，对H460肿瘤中的总暴露量贡献20%至49%，但在血浆中<5%。给予的他西多丁剂量中不到5%转化为他西多丁-C-羧酸盐，在接受LOX和H460治疗的动物之间没有明显差异。Z-脯氨酰脯氨醛的存在使转化为他西多丁-C-羧酸盐的他西多丁量从5.5%降至0.90%，减少了近80%。给予他西多丁-C-羧酸盐后，其半衰期以分钟计，而给予他西多丁后观察到的半衰期以小时计。他西多丁-C-羧酸盐的消除不依赖于他西多丁的药代动力学，这表明从细胞外排到血浆中的速率是其消除的限速步骤。他西多丁-C-羧酸盐也进一步代谢为去脯氨酰他西多丁-C-羧酸盐，尽管代谢物比例<10%。用Z-脯氨酰脯氨醛预处理完全消除了他西多丁的抗肿瘤活性，表明该代谢产物是活性的主要部分，并且尽管他西多丁本身在体外具有活性，但他西多丁主要起前药的作用。
