Change in pharmacokinetic and pharmacodynamic behavior of gemcitabine in human tumor xenografts upon entrapment in vesicular phospholipid gels
Change in pharmacokinetic and pharmacodynamic behavior of gemcitabine in human tumor xenografts upon entrapment in vesicular phospholipid gels
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DOI：
10.1007/s00280-002-0428-4
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发表时间：
2002-05-01
影响因子：
3
通讯作者：
Massing, U
中科院分区：
文献类型：
--
作者：
Moog, R;Burger, AM;Massing, U
目的：体内药代动力学(PK)。比较了吉西他滨新脂质体(GemLip)和传统吉西他滨(GernConv)脂质体的生物分布和抗肿瘤活性。方法：吉西他滨被包裹在由致密脂质体组成的囊状磷脂凝胶中。再分散的含GemLip的VPG由33%的脂质体和67%的游离吉他滨组成。比较了GemLip和GemConv对皮下生长的人软组织肉瘤SXF 1301和原位生长的人膀胱癌BXF 1299T的体内疗效。用放射性标记药物和脂质在SXF 1301荷瘤裸鼠体内评价PK和生物分布。结果：吉西他滨剂量为6~9 mg/kg(第1、8、15天；剂量接近MTD)时，GemLip在SXF 1301中具有很高的活性。在6 mg/kg剂量组中，8只小鼠中有7只肿瘤完全缓解。等摩尔剂量的GemConv仅导致中等程度的肿瘤生长抑制。即使在等毒剂量(第1、8和15天给药360 mg/kg，或第1、5和8天给药120 mg/kg)下，GemConv的活性也低于GemLip。此外，GemLip在6 mg/kg的BXF 1299T原位生长膀胱癌模型中具有活性，并可防止远处器官转移。在PK研究中，GemLip的血浆AUC(1680毫克·小时/毫升)是GemConv(47.6毫克·小时/毫升)的35倍。游离吉西他滨的血清半衰期为0.15h，脂质体吉西他滨(6 mg/kg)的血清半衰期为13.3h。此外，注射GemLip后肿瘤中的吉西他滨水平是注射GemConv后的四倍。结论：GemLip是一种高效的吉西他滨给药系统，吉西他滨的药代动力学和PK均优于吉西他滨。体内药效的增强可能是通过缓释和被动肿瘤靶向来实现的。
Purpose:The in vivo pharmacokinetics (PK). biodistribution and antitumor activity of a new liposomal formulation of gemcitabine (GemLip) were compared to the conventional (clinical) formulation of gemcitabine (GernConv). Methods: Gemcitabine was entrapped in a vesicular phospholipid gel fVPG) consisting of densely packed liposomes. Redispersed VPG containing GemLip consisted of 33% liposomally entrapped and 67% free genicitabine. The in vivo efficacies of GemLip and GemConv were compared using the subcutaneously growing human soft tissue sarcoma SXF 1301 and the orthotopically growing human bladder cancer BXF 1299T. PK and biodistribution were evaluated using radiolabeled drug, and lipid in SXF 1301 tumor-bearing nude mice. Results: GemLip was highly active in SXF 1301 at a gemcitabine dose of 6-9 mg/kg (days 1, 8 and 15; dose near the MTD). In the 6-mg/kg groups, complete tumor remissions were observed in seven of eight mice. Equimolar doses of GemConv resulted in only moderate tumor growth inhibition. Even at equitoxic doses (360 mg/kg given on days 1, 8 and 15, or 120 mg/kg on days 1, 5 and 8) GemConv was less active than GemLip. Furthermore, GemLip was active in the orthotopically growing BXF 1299T bladder cancer model at 6 mg/kg and prevented distant organ metastasis. In the PK Study, GemLip achieved a 35-fold higher plasma AUC (1680 mg(.)h/ml) than GemConv (47.6 mg(.)h/ml). The serum half-lives were 0.15 h for free gemcitabine and 13.3 h for liposomal gemcitabine (6 mg/kg each i.v.). Moreover, gemcitabine levels In tumors were fourfold higher following injection of GemLip than following injection of GemConv. Conclusions:GemLip is a highly effective gemcitabine delivery system which results in superior gemcitabine pharmacodynainics and PK than GemConv. The enhanced in vivo efficacy might be explained by sustained release and passive tumor targeting.