Hilger R A, Jacek G, Oberhoff C, Kredtke S, Baumgart J, Seeber S, Scheulen M E
Innere Klinik und Poliklinik (Tumorforschung), Universitätsklinikum Essen, Westdeutsches Tumorzentrum, Germany.
Cancer Chemother Pharmacol. 2000;45(6):483-8. doi: 10.1007/s002800051023.
Treosulfan (L-threitol-1,4-bis-methanesulfonate, Ovastat) is a prodrug of a bifunctional alkylating agent with activity in ovarian carcinoma and other solid tumors. In a pharmacologic study of the bioavailability of treosulfan in a capsule formulation, patients with relapsed ovarian carcinoma were treated with alternating doses of oral and intravenous (i.v.) treosulfan of 1.5 or 2.0 g daily for 5 to 8 days.
A sensitive method for the determination of treosulfan in plasma and urine by reversed-phase high-performance liquid chromatography had previously been developed. Pharmacokinetic analyses of treosulfan were carried on plasma and urine samples from 20 i.v. courses and 20 courses of oral administration.
The bioavailability ratio (f) of oral to i.v. administration was calculated as 0.97 +/- 0.18 (mean +/- SD) using the values AUC oral = 82.1 +/- 39.4 microg/ml h and AUC i.v. = 85.4 +/- 30.3 microg/ml h. The peak plasma concentration cmax (29 +/- 14 microg/ml vs 65 +/- 23 microg/ml) was significantly (P < 0.01) higher after i.v. administration and the tmax after oral administration was 1.5 +/- 0.34 h. The terminal half-life of treosulfan was about 1.8 h. The mean urinary excretion of the parent compound was about 15% of the administered total dose over 24 h (range 6-26%).
The high and relatively constant bioavailability of treosulfan indicates that capsules provide a satisfactory noninvasive treatment alternative. A feasible and reliable oral treosulfan formulation could provide the basis for the development of long-term low-dose outpatient treatment of patients with malignant diseases.
曲奥舒凡（L-苏糖醇-1,4-双甲磺酸酯，Ovastat）是一种双功能烷化剂的前体药物，对卵巢癌和其他实体瘤具有活性。在一项关于曲奥舒凡胶囊制剂生物利用度的药理学研究中，复发卵巢癌患者接受了每日1.5或2.0 g口服和静脉注射（i.v.）曲奥舒凡交替剂量治疗，持续5至8天。
此前已开发出一种通过反相高效液相色谱法测定血浆和尿液中曲奥舒凡的灵敏方法。对20个静脉注射疗程和20个口服疗程的血浆和尿液样本进行了曲奥舒凡的药代动力学分析。
使用AUC口服=82.1±39.4μg/ml·h和AUC静脉注射=85.4±30.3μg/ml·h的值，计算出口服给药与静脉注射给药的生物利用度比值（f）为0.97±0.18（平均值±标准差）。静脉注射给药后血浆峰浓度cmax（29±14μg/ml对65±23μg/ml）显著更高（P<0.01），口服给药后的tmax为1.5±0.34 h。曲奥舒凡的终末半衰期约为1.8 h。母体化合物的平均尿排泄量在24小时内约为给药总剂量的15%（范围6 - 26%）。
曲奥舒凡具有较高且相对恒定的生物利用度，表明胶囊制剂提供了一种令人满意的非侵入性治疗选择。一种可行且可靠的口服曲奥舒凡制剂可为恶性疾病患者的长期低剂量门诊治疗开发提供基础。
